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Online Library: Cancer

The following pages provide an overview of the most recent research and clinical studies about the health benefits of micronutrients in fighting cancer. This collection of scientific facts proves that anyone who privately or publicly questions the health value of micronutrients does not serve YOUR health, or the health of the people, but rather the multi-billion dollar investment 'business with disease' based on patented pharmaceutical drugs.

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Vitamin or antioxidant intake (or serum level) and risk of cervical neoplasm: a meta-analysis

Source: BJOG 2011 July 12; [Epub ahead of print].

Author: Myung SK, Ju W, et al.

Affiliation: Cancer Epidemiology Branch, Research Institute, Smoking Cessation Clinic and Center for Cancer Prevention and Detection, Hospital, National Cancer Center, Goyang, Korea).

Abstract: In this meta-analysis which included data gathered from 22 case-control studies, involving a total of 10,073 subjects, which investigated an association between vitamin or antioxidant intake (or serum level) and cervical neoplasm risk, results found that intakes of vitamin B12 (OR=0.35), vitamin C (OR=0.67), vitamin E (OR=0.56), and beta-carotene (OR=0.68) were found to be associated with a significantly reduced odds ratio of cervical neoplasm. The authors state, "The findings of this meta-analysis indicate that overall, there were preventive effects of vitamin or antioxidant intake on cervical neoplasm’s in case-control studies."

Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression

Source: Cancer causes & control 2011, Jul 15.[Epub ahead of print].

Author: Fulan H, Changxing J, et al.

Affiliation: Department of Epidemiology, Public Health College, Harbin Medical University, China.

Abstract: In this review, the authors analyzed data from 51 studies examining the relationships between intakes of retinol, vitamin A, vitamin C, and vitamin E on risk of breast cancer, and found that the risk of breast cancer was reduced by 17% in those with the highest vitamin A intake (compared to the lowest, pooled OR=0.83). Furthermore, dietary vitamin A, dietary vitamin E, and total vitamin E intakes all reduced the risk of breast cancer when results from all the studies were pooled, but became non-significant when data from the cohort studies was pooled. The authors conclude, "...the total intake of vitamin A and retinol could reduce breast cancer risk."

Dietary antioxidants and risk of Barrett's esophagus and adenocarcinoma of the esophagus in an Australian population

Source: International Journal of Cancer 2013 Jul;133(1):214-24

Author: Ibiebele TI, Hughes MC, Nagle CM, Bain CJ, Whiteman DC, Webb PM

Affiliation: Population Health Department, Queensland Institute of Medical Research, Royal Brisbane Hospital, Brisbane, QLD, 4029, Australia.

Abstract: While dietary antioxidants are emerging as potentially modifiable risk factors for esophageal adenocarcinoma (EAC), studies on dietary antioxidants and its precursor Barrett's esophagus (BE) are limited. The present study extends previous work on BE by investigating risks of nondysplastic BE, dysplastic BE and EAC associated with intake of antioxidants such as vitamin C, vitamin E, β-carotene, and selenium. Age and sex matched control subjects (n=577 for BE; n=1,507 for EAC) were sampled from an Australian population register. Information on demography, and well established EAC risk factors were obtained using self-administered questionnaires. Intake of antioxidants for patients newly diagnosed with nondysplastic BE (n=266), dysplastic BE (n=101), or EAC (n=299), aged 18-79 years, were obtained using a food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable adjusted logistic regression models. High intake of β-carotene from food and supplement sources combined was inversely associated with risk of dysplastic BE (OR Q4 vs. Q1=0.45; 95%CI: 0.20-1.00). High intake of vitamin E from food sources (OR Q4 vs. Q1=0.43; 95%CI: 0.28-0.67), from food and supplements combined (OR Q4 vs. Q1=0.64; 95%CI: 0.43-0.96), and a high antioxidant index score were inversely associated with risk of EAC. We found no significant trends between intake of β-carotene, vitamin C, vitamin E, and selenium and risk of nondysplastic or dysplastic BE. However, our data suggest that a high intake of β-carotene may be associated with decreased risk of dysplastic BE.

Green tea intake is associated with urinary estrogen profiles in Japanese-American women.

Source: Nutr J. 2013 Feb 15;12(1):25.

Author: Fuhrman BJ, Pfeiffer RM, Wu AH, Xu X, Keefer LK, Veenstra TD, Ziegler RG.

Affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Abstract: Intake of green tea may reduce the risk of breast cancer; polyphenols in this drink can influence enzymes that metabolize estrogens, known causal factors in breast cancer etiology. The authors examined the associations of green tea intake (<1 time/week, 1-6 times weekly, or 7+ times weekly) with urinary estrogens and estrogen metabolites in a cross-sectional sample of healthy Japanese American women, including 119 premenopausal women in luteal phase and 72 postmenopausal women. In postmenopausal women, urinary estrone and estradiol were approximately 20% and 40% lower in women drinking green tea daily compared to those drinking <1 time/week. Adjustment for potential confounders (age at menarche, parity/age at first birth, body mass index, Asian birthplace, soy) did not change these associations. Conclusion: Findings suggest that intake of green tea may modify estrogen metabolism or conjugation and in this way may influence breast cancer risk.

Effect of eicosapentaenoic acid, an omega-3 polyunsaturated fatty acid, on UVR-related cancer risk in humans. An assessment of early genotoxic markers.

Source: Carcinogenesis. 2003 May;24(5):919-25.

Author: Rhodes LE, Shahbakhti H, Azurdia RM, Moison RM, Steenwinkel MJ, Homburg MI, Dean MP, McArdle F, Beijersbergen van Henegouwen GM, Epe B, Vink AA.

Affiliation: Photobiology Unit, Dermatology Centre, University of Manchester, UK.

Abstract: Dietary omega-3 polyunsaturated fatty acids (omega-3 PUFAs) protect against photocarcinogenesis in animals, but prospective human studies are scarce. The mechanism(s) underlying the photoprotection are uncertain, although omega-3 PUFAs may influence oxidative stress. The authors examined the effect of supplementation on a range of indicators of ultraviolet radiation (UVR)-induced DNA damage in humans, and assessed effect on basal and post-UVR oxidative status. In a double-blind randomized study, 42 healthy subjects took 4 g daily of purified omega-3 PUFA, eicosapentaenoic acid (EPA), or monounsaturated, oleic acid (OA), for 3 months. No consistent pattern of alteration in basal and UVR-exposed skin content of the antioxidants glutathione, vitamins E and C or lipid peroxidation, was seen on supplementation. Sunburn sensitivity was reduced on EPA, the UVR-induced erythemal threshold rising from a mean of 36 (SD 10) mJ/cm(2) at baseline to 49 (16) mJ/cm(2) after supplementation. Moreover, UVR-induced skin p53 expression, assessed immunohistochemically at 24 h post-UVR exposure, fell from a mean of 16 (SD 5) positive cells/100 epidermal cells at baseline to 8 (4) after EPA supplementation. Results en conclusion: No significant changes were seen in any of the above parameters following OA supplementation. Reduction in this range of early markers, i.e. sunburn, UVR-induced p53 in skin and strand breaks in PBL, indicate protection by dietary EPA against acute UVR-induced genotoxicity; longer-term supplementation might reduce skin cancer in humans.

Effect of eicosapentaenoic acid, an omega-3 polyunsaturated fatty acid, on UVR-related cancer risk in humans. An assessment of early genotoxic markers.

Source: Carcinogenesis. 2003 May;24(5):919-25.

Author: Rhodes LE, Shahbakhti H, Azurdia RM, Moison RM, Steenwinkel MJ, Homburg MI, Dean MP, McArdle F, Beijersbergen van Henegouwen GM, Epe B, Vink AA.

Affiliation: Photobiology Unit, Dermatology Centre, University of Manchester, UK.

Abstract: Dietary omega-3 polyunsaturated fatty acids (omega-3 PUFAs) protect against photocarcinogenesis in animals, but prospective human studies are scarce. The mechanism(s) underlying the photoprotection are uncertain, although omega-3 PUFAs may influence oxidative stress. The authors examined the effect of supplementation on a range of indicators of ultraviolet radiation (UVR)-induced DNA damage in humans, and assessed effect on basal and post-UVR oxidative status. In a double-blind randomized study, 42 healthy subjects took 4 g daily of purified omega-3 PUFA, eicosapentaenoic acid (EPA), or monounsaturated, oleic acid (OA), for 3 months. No consistent pattern of alteration in basal and UVR-exposed skin content of the antioxidants glutathione, vitamins E and C or lipid peroxidation, was seen on supplementation. Sunburn sensitivity was reduced on EPA, the UVR-induced erythemal threshold rising from a mean of 36 (SD 10) mJ/cm(2) at baseline to 49 (16) mJ/cm(2) after supplementation. Moreover, UVR-induced skin p53 expression, assessed immunohistochemically at 24 h post-UVR exposure, fell from a mean of 16 (SD 5) positive cells/100 epidermal cells at baseline to 8 (4) after EPA supplementation. Results en conclusion: No significant changes were seen in any of the above parameters following OA supplementation. Reduction in this range of early markers, i.e. sunburn, UVR-induced p53 in skin and strand breaks in PBL, indicate protection by dietary EPA against acute UVR-induced genotoxicity; longer-term supplementation might reduce skin cancer in humans.

Intake of omega-3 and omega-6 fatty acids and risk of basal and squamous cell carcinomas of the skin: a longitudinal community-based study in Australian adults.

Source: Nutr Cancer. 2012;64(7):982-90.

Author: Wallingford SC, van As JA, Hughes MC, Ibiebele TI, Green AC, van der Pols JC.

Affiliation: Cancer and Population Studies Group, Queensland Institute of Medical Research, Brisbane, Australia.

Abstract: Intake of omega-3 and omega-6 fatty acids may modify the risk of basal and squamous cell carcinoma of the skin (BCC and SCC), but population-based evidence is limited and inconsistent. The authors examined prospectively associations between intake of omega-3 and omega-6 fatty acids estimated from food frequency questionnaires and BCC and SCC incidence among 1322 randomly selected adults in Nambour, Australia. Relative risks (RR) and 95% confidence intervals (CI) were estimated based on histologically confirmed tumors diagnosed between 1997 and 2007. Incidence of BCC was lowest in the middle third of both total omega-6 intake and linoleic acid intake compared with the lowest third of intake. Evidence for associations with SCC was weak, though persons with arachidonic acid intake in the middle third had a marginally increased risk of SCC. Consumption of omega-3 fatty acids was not associated with subsequent skin cancer risk. Suggestion that intake of arachidonic acid may be associated with increased SCC incidence and total omega-6 with reduced BCC from this study is still highly uncertain and may be due to chance. These data do not support an association between these fatty acids and risk of BCC or SCC.

Dietary fat intake and risk of skin cancer: a prospective study in Australian adults.

Source: Int J Cancer. 2009 Oct 1;125(7):1678-84.

Author:

Affiliation: Cancer and Population Studies Group, Clive Berghofer Cancer Research Centre, Queensland Institute of Medical Research, Herston, Queensland, Australia.

Abstract: Although intakes of dietary fat have been associated with both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin, the evidence is sparse and inconsistent. This study prospectively investigated the association between total dietary fat; saturated, polyunsaturated and monounsaturated fatty acids; and percent energy from fat in relation to BCC and SCC of the skin. At baseline in 1992, total fat intake and intake of fatty acids were assessed in an Australian community-based longitudinal study, using a validated semi-quantitative food frequency questionnaire in 1,057 adult residents (aged 25-75 years) in Nambour, Queensland. Information on demography, sun-sensitivity history and sun exposure factors were obtained using self-administered questionnaires. Associations with BCC and SCC in terms of persons newly affected and of tumor counts were assessed based on incident, histologically-confirmed tumors occurring between 1992 and 2002. No significant linear trends were observed in overall risk of BCC or SCC of the skin with increasing total fat intake. However, in participants with a history of skin cancer, total fat intake was associated with increased numbers of SCC tumors comparing the highest to lowest tertile. Conclusion: SCC tumor risk increased as total fat intake increased in people with a history of skin cancer. Dietary fats were not associated with BCC occurrence.

Improvement of genetic stability in lymphocytes from Fanconi anemia patients through the combined effect of á-lipoic acid and N-acetylcysteine.

Source: Orphanet J Rare Dis. 2012 May 16;7:28. doi: 10.1186/1750-1172-7-28.

Author: Ponte F, Sousa R, Fernandes AP, Gonçalves C, Barbot J, Carvalho F, Porto B.

Affiliation: Chemistry and Technology Network (REQUIMTE), Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal.

Abstract: Fanconi Anemia (FA) is a rare genetic disorder, characterized by progressive bone marrow failure and increased predisposition to cancer. Despite being highly heterogeneous, all FA patients are hypersensitive to alkylating agents, in particular to 1,2:3,4-diepoxybutane (DEB), and to oxidative damage. Recent studies point to defective mitochondria in FA cells, which is closely related with increased production of reactive oxygen species (ROS) and concomitant depletion of antioxidant defenses, of which glutathione is a well-known biomarker. The objective of this study was to evaluate the putative protective effect of á-lipoic acid (á-LA), a mitochondrial protective agent, and N-acetylcysteine (NAC), a direct antioxidant and a known precursor for glutathione synthesis, in spontaneous and DEB-induced chromosome instability (CI) in lymphocyte cultures from FA patients. For that purpose, lymphocyte cultures from 15 FA patients and 24 healthy controls were pre-treated with 20 ìM á-LA, 500 ìM NAC and á-LA plus NAC at the same concentrations, and some of them were exposed to DEB (0.05 ìg/ml). A hundred metaphases per treatment were scored to estimate the relative frequency of spontaneous and DEB-induced chromosome breakage. The obtained results revealed that a cocktail of á-LA and NAC can drastically improve the genetic stability in FA lymphocytes in vitro, decreasing CI by 60% and 80% in cultures from FA patients and FA mosaic/chimera patients, respectively. These results suggest that the studied cocktail can be used as a prophylactic approach to delay progressive clinical symptoms in FA patients caused by CI, which can culminate in the delay of the progressive bone marrow failure and early cancer development.

Protective effect of acetyl-l-carnitine and á-lipoic acid against the acute toxicity of diepoxybutane to human lymphocytes.

Source: Toxicology. 2011 Oct 28;289(1):52-8.

Author: Ponte F, Carvalho F, Porto B.

Affiliation: REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua Anibal Cunha, 164, 4099-030 Porto, Portugal.

Abstract: The biotransformation and oxidative stress may contribute to 1,2:3,4-diepoxybutane (DEB)-induced toxicity to human lymphocytes of Fanconi Anemia (FA) patients. Thus, the identification of putative inhibitors of bioactivation, as well as the determination of the protective role of oxidant defenses, on DEB-induced toxicity, can help to understand what is failing in FA cells. The authors studied the contribution of several biochemical pathways for DEB-induced acute toxicity in human lymphocyte suspensions, by using inhibitors of epoxide hydrolases, inhibitors of protective enzymes as glutathione S-transferase and catalase, the depletion of glutathione (GSH), and the inhibition of protein synthesis; and a variety of putative protective compounds, including antioxidants, and mitochondrial protective agents. This study reports two novel findings: (i) it was clearly evidenced, for the first time, that the acute exposure of freshly isolated human lymphocytes to DEB results in severe GSH depletion and loss of ATP, followed by cell death; (ii) acetyl-l-carnitine elicits a significant protective effect on DEB induced toxicity, which was potentiated by á-lipoic acid. Collectively, these findings contribute to increase our knowledge of DEB-induce toxicity and will be very useful when applied in studies with lymphocytes from FA patients, in order to find out a protective agent against spontaneous and DEB-induced chromosome instability.

Pilot study of Panax quinquefolius (American ginseng) to improve cancer-related fatigue: a randomized, double-blind, dose-finding evaluation: NCCTG trial N03CA.

Source: Support Care Cancer. 2010 Feb;18(2):179-87.

Author: Barton DL, Soori GS, Bauer BA, Sloan JA, Johnson PA, Figueras C, Duane S, Mattar B, Liu H, Atherton PJ, Christensen B, Loprinzi CL.

Affiliation: Mayo Clinic and Mayo Foundation, 200 First Street, SW, Rochester, MN 55905, USA.

Abstract: This pilot trial sought to investigate whether any of 3 doses of American ginseng (Panax quinquefolius) might help cancer-related fatigue. A secondary aim was to evaluate toxicity. Eligible adults with cancer were randomized in a double-blind manner, to receive American ginseng in doses of 750, 1,000, or 2,000 mg/day or placebo given in twice daily dosing over 8 weeks. Outcome measures included the Brief Fatigue Inventory, vitality subscale of the Medical Outcome Scale Short Form-36 (SF-36), and the Global Impression of Benefit Scale at 4 and 8 weeks. 290 patients were accrued to this trial. Nonsignificant trends for all outcomes were seen in favor of the 1,000- and 2,000-mg/day doses of American ginseng. Area under the curve analysis of activity interference from the Brief Fatigue Inventory was 460-467 in the placebo group and 750 mg/day group versus 480-551 in the 1,000- and 2,000-mg/day arms, respectively. Change from baseline in the vitality subscale of the SF-36 was 7.3-7.8 in the placebo and the 750-mg/day arm, versus 10.5-14.6 in the 1,000- and 2,000-mg/day arms. Over twice as many patients on ginseng perceived a benefit and were satisfied with treatment over those on placebo. There were no significant differences in any measured toxicities between any of the arms. Conclusion: There appears to be some activity and tolerable toxicity at 1,000-2,000 mg/day doses of American ginseng with regard to cancer-related fatigue. Thus, further study of American ginseng is warranted.

Multivitamins in the prevention of cancer in men: the Physicians' Health Study II randomized controlled trial.

Source: http://www.ncbi.nlm.nih.gov/pubmed/23162860

Author: Gaziano JM, et al.

Affiliation: Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Abstract: Multivitamin preparations are the most common dietary supplement, taken by at least one-third of all US adults. Observational studies have not provided evidence regarding associations of multivitamin use with total and site-specific cancer incidence or mortality. The objective of this study was to determine whether long-term multivitamin supplementation decreases the risk of total and site-specific cancer events among men. The study was a large-scale, randomized, double-blind, placebo controlled trial (Physicians" Health Study II) of 14 641 male US physicians initially aged 50 years or older (mean [SD] age, 64.3 [9.2] years), including 1312 men with a history of cancer at randomization, enrolled in a common multivitamin study that began in 1997 with treatment and follow-up through June 1, 2011. Daily multivitamins or a placebo was used as an intervention. Total cancer (excluding nonmelanoma skin cancer), with prostate, colorectal, and other site-specific cancers among the secondary end points was measured. During a median (interquartile range) follow-up of 11.2 (10.7-13.3) years, there were 2669 men with confirmed cancer, including 1373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer. There was no significant effect of a daily multivitamin on prostate cancer, colorectal cancer, or other site-specific cancers. There was no significant difference in the risk of cancer mortality. Daily multivitamin use was associated with a reduction in total cancer among 1312 men with a baseline history of cancer, but this did not differ significantly from that among 13 329 men initially without cancer. The conclusion of this large prevention trial of male physicians is that daily multivitamin supplementation modestly but significantly reduced the risk of total cancer.

Amino Acids and Cancer

Antitumor Effect of Lysine–Isopeptides

Source: Cancer Cell International 2002, 2:4

Author: B. Szende,1 Gy Szöká,2 E. Tyihá,3 K. Pál,2 R. Gáborjányi,2 M. Almás2 and A.R. Khlafulla2

Affiliation: 1st Institute of Pathology and Experimental Cancer Research, Joint Research Organisation, Hungarian Academy of Sciences and Semmelweis University, H-1085. Budapest, Üllõi út 26, Hungary,1 Department of Organic Chemistry, Lóránt Eötvös University, H-1518. Budapest 112, P.O. Box 32, Hungary,2 Research Institute of Plant Protection, Hungarian Academy of Sciences, H-1022. Budapest, Herman O. ut 15., Hungary 3

Abstract: Isopeptides (ε-peptides) of lysine, with a given Mw and low polydispersity (10–400 units), were synthesized to study the relationship between their chemical structure and biological effect. The designed compounds were of high purity, low polydispersity and high stereochemical purity. The effect of the compounds was tested on a human erythroleukemia cell line (K-562) and on four transplantable mouse tumors (L1210 lymphoid leukemia, P38 macrophage derived tumor, Ehrlich ascites carcinoma, Lewis lung tumor /LLT/). The polymers of polymerisation degree 80–120 (Mw 10.2–15.4 KD) showed the strongest antiproliferative effect both on K562 cells and the tumors growing in vivo. This effect was manifest with a significantly higher survival rate as compared to the control (L1210, P38, Ehrlich ascites), furthermore, by a decrease in the number and size of liver and lung metastases (LLT).

Lysine-Specific Demethylase 1 Is Strongly Expressed in Poorly Differentiated Neuroblastoma: Implications for Therapy

Source: Cancer Res 2009; 69: 2065-2071

Author: Johannes H. Schulte,1 Soyoung Lim,3 Alexander Schramm,1 Nicolaus Friedrichs,3 Jan Koster,4 Rogier Versteeg,4 Ingrid Ora,4,5 Kristian Pajtler,1 Ludger Klein-Hitpass,2 Steffi Kuhfittig-Kulle,1 Eric Metzger,6 Roland Schüle,6 Angelika Eggert,1 Reinhard Buettner3 and Jutta Kirfe3

Affiliation: Department of Paediatric Oncology and Hematology, University Children's Hospital Essen;1 Institute of Cell Biology, University Hospital of Essen, Essen, Germany;2 Institute of Pathology, University of Bonn, Bonn, Germany;3 Department of Human Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands;4 Department of Pediatric Oncology and Hematology, Lund University Hospital, Lund, Sweden;5 Center for Clinical Research, Freiburg University Medical Center, Freiburg, Germany6

Abstract: Recently, several histone demethylases were identified catalyzing the removal of methyl groups from histone H3 lysine residues and thereby influencing gene expression. Neuroblastomas continue to remain a clinical challenge despite advances in multimodal therapy. This study addresses the functional significance of the chromatin-modifying enzyme lysine-specific demethylase 1 (LSD1) in neuroblastoma. LSD1 expression correlated with adverse outcome and was inversely correlated with differentiation in neuroblastic tumors. The study provides the first evidence that a histone demethylase, LSD1, is involved in maintaining the undifferentiated, malignant phenotype of neuroblastoma cells. The study shows that inhibition of LSD1 reprograms the transcriptome of neuroblastoma cells and inhibits neuroblastoma xenograft growth. The results suggest that targeting histone demethylases may provide a novel option for cancer therapy.

Deregulation of Histone Lysine Methyltransferases Contributes to Oncogenic Transformation of Human Bronchoepithelial Cells

Source: Cancer Cell Int. 2008 Nov 3;8:15.

Author: Watanabe H, Soejima K, Yasuda H, Kawada I, Nakachi I, Yoda S, Naoki K, Ishizaka A.

Affiliation: Department of Pulmonary Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Abstract: To date, several histone lysine methyltransferases (HKMTs) have been identified and histone lysine methylation is now considered to be a critical regulator of transcription. However, still relatively little is known about the role of HKMTs in tumorigenesis. The study showed that differential HKMT expression in a lung cancer model in which normal human bronchial epithelial (NHBE) cells expressing telomerase, SV40 large T antigen, and Ras were immortal, formed colonies in soft agar, and expressed specific HKMTs for H3 lysine 9 and 27 residues but not for H3 lysine 4 residue. The results indicate the potential of these HKMTs in addition to the other targets for epigenetics such as DNMTs and HDACs to be interesting therapeutic targets.

Suppression of Proline-Directed Protein Kinase FA Expression Inhibits the Growth of Human Chronic Myeloid leukaemia Cells

Source: British Journal of Cancer (2000) 82, 1480–1484.

Author: C-P Hsu, S-F Hsueh, C-C Yang, and S-D Yang

Affiliation: Department of Life Science, National Tsing Hua University, Hsinchu, 30013, Taiwan, Republic of China

Abstract: This study explored the potential role of PDPK FAin leukaemia cell growth by investigating the effects of partial inhibition of this kinase on the malignant phenotype of human chronic myeloid leukaemia cells (K562). Cloning of PDPK FAcDNA and its recombinant antisense expression vector and PDPK FA-specific antibody were successfully developed. The results demonstrate that specific antisense suppression of PDPK FAis sufficient to interfere with the growth of K562 cells, indicating that PDPK FAis essential for human chronic myeloid leukaemia cell growth. © 2000 Cancer Research Campaign

Arginine and Proline Alleles of the p53 Gene are Associated with Different Locations of Gastric Cancer

Source: Hepato-Gastroenterology, 2005, vol. 52, (No6), pp. 944-948,

Author: LAI Kuang-Chi;1,2 CHEN Wen-Chi;3,4 TSAI Fuu-Jen;3 LI Shuan-Yow;2,5 JENG Long-Bin1

Affiliation: Department of Surgery, China Medical University Hospital,1 Graduate Institute of Medicine, Chung-Shan Medical University, Taichung,2 Department of Pediatric and Medical Genetics, China Medical University Hospital,3 Department of Urology, China Medical University Hospital,4 Department of Life Sciences, Chung-Shan Medical University, Taichung,5 Taiwan, China

Abstract: This study of 51 patients and 59 control subjects evaluated the risk factors associated with p53 codon 72 polymorphism and gastric cancer carcinogenesis. The p53 gene codon 72 polymorphism was analyzed by polymerase chain reaction (PCR). The results of polymorphic genotype were stratified with the above risk factors and the associations were also examined. The proline allele at p53 codon 72 is associated with adenocarcinoma of the gastric cardia, and the arginine allele is associated with cancer of the antral and corpus locations. These findings suggest that different genotypes of the p53 gene in different locations of stomach might implicate a different cause of tumor growth.

Proline Oxidase Induces Apoptosis in Tumor Cells, and its Expression is Frequently Absent or Reduced in Renal Carcinoma

Source: J. Biol. Chem., March 14, 2003; Vol. 278, Issue 11, 9784-9789,

Author: Steve A. Maxwell and Armando Rivera

Affiliation: Texas A&M University System Health Science Center, Department of Pathology and Laboratory Medicine, College Station, Texas

Abstract: The study provides evidence implicating a role for proline oxidase in renal carcinoma that was observed in 8 of 12 primary renal cell carcinomas, with respect to their normal tissue counterparts. The study shows that a proline oxidase antisense vector repressed p53-induced up-regulation of proline oxidase, released of cytochrome c from mitochondria, and apoptosis in 786-0 renal carcinoma cells. Taken together, these findings support a role for proline oxidase as a downstream effector in p53-mediated apoptosis. The study hypothesizes that its altered expression can contribute to the development of renal carcinomas.

Bladder Cancer

Megadose vitamins in bladder cancer: a double-blind clinical trial.

Source: J Urol 1994;151(1):21-6.

Author: Lamm DL, Riggs DR, Shriver JS, vanGilder PF, Rach JF, DeHaven JI.

Affiliation: Department of Urology, West Virginia University School of Medicine, Morgantown.

Abstract: Epidemiological and laboratory studies suggest that vitamin supplements may be helpful in the prevention of some cancers but clinical trials to date have failed to demonstrate protection with naturally occurring vitamins. Without substantiation of the highly touted benefits of vitamins, few physicians who care for cancer patients have recommended their use. A total of 65 patients with biopsy confirmed transitional cell carcinoma of the bladder enrolled in a randomized comparison of intravesical bacillus Calmette-Guerin (BCG) with or without percutaneous administration was also randomized by closed envelope to therapy with multiple vitamins in the recommended daily allowance (RDA) versus RDA multivitamins plus 40,000 units vitamin A, 100 mg. vitamin B6, 2,000 mg. vitamin C, 400 units vitamin E and 90 mg. zinc. The addition of percutaneous BCG did not significantly lessen tumor recurrence but recurrence after 10 months was markedly reduced in patients receiving megadose vitamins. The 5-year estimates of tumor recurrence are 91% in the RDA arm and 41% in the megadose arm (p = 0.0014, Mantel-Cox). Overall recurrence was 24 of 30 patients (80%) in the RDA arm and 14 of 35 (40%) in the high dose arm (p = 0.0011, 2-tailed Fisher's exact test). Megadose vitamins A, B6, C and E plus zinc decrease bladder tumor recurrence in patients receiving BCG immunotherapy. Further research will be required to identify which ingredient(s) provide this protection.

Prospective study of dietary supplements, macronutrients, micronutrients, and risk of bladder cancer in US men.

Source: Am J Epidemiol. 2000;152(12):1145-53.

Author: Michaud DS, Spiegelman D, Clinton SK, Rimm EB, Willett WC, Giovannucci E.

Affiliation: Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.

Abstract: Data derived from laboratory investigations suggest that a number of dietary variables may contribute to bladder carcinogenesis. Although bladder cancer is the fourth leading cause of cancer in men in the United States, dietary studies are few. The authors examined the relations between intakes of macro- and micronutrients and the risk of bladder cancer among men in the prospective Health Professionals Follow-Up Study. Total vitamin E intake and vitamin E supplements were inversely associated with risk. In addition, a dose-response relation was observed for duration of vitamin E supplement use. A suggestive inverse association was seen with dose of vitamin C supplement use. More studies are needed to determine the role of vitamins E and C supplement intake in bladder carcinogenesis.

Nutrient intake in relation to bladder cancer among middle-aged men and women.

Source: Am J Epidemiol. 1996; 144(5):485-95.

Author: Bruemmer B, White E, Vaughan TL, Cheney CL.

Affiliation: Fred Hutchinson Cancer Research Center, Division of Clinical Research, Seattle, WA, USA.

Abstract: This population-based case-control study examined the association between selected nutrients, foods, and diet behaviors and bladder cancer. Analyses were conducted by logistic regression analysis and included adjustment for age, sex, smoking (current, former, never), and county. The use of multivitamin supplements daily over the 10-year period ending 2 years before diagnosis versus no use was associated with a decreased risk of bladder cancer as was use of supplemental vitamin C. Increased intake of fruit was associated with a decreased risk of bladder cancer, while increased use of fried foods was associated with an increased risk of bladder cancer. This study provides modest evidence that certain nutrients, foods, and supplementation may affect the incidence of bladder cancer.

Diet and bladder cancer: a meta-analysis of six dietary variables.

Source: Am J Epidemiol. 2000;151(7):693-702.

Author: Steinmaus CM, Nuñez S, Smith AH.

Affiliation: Division of Occupational and Environmental Medicine, University of California at San Francisco, USA.

Abstract: In 1996, more than 300,000 new cases of bladder cancer were diagnosed worldwide. Besides tobacco smoking, occupation, and other factors, diet may play a role in causation of this illness. The authors performed a meta-analytical review of epidemiologic studies linking six dietary factors to bladder cancer. These factors include retinol, beta-carotene, fruits, vegetables, meat, and fat. Increased risks of bladder cancer were associated with diets low in fruit intake and slightly increased risks were associated with diets low in vegetable intake. Elevated risks were identified for diets high in fat intake but not for diets high in meat intake. No increased risks were found for diets low in retinol or beta-carotene intake. These results suggest that a diet high in fruits and vegetables and low in fat intake may help prevent bladder cancer, but the individual dietary constituents that reduce the risks remain unknown.

Inhibition of bladder tumor growth by the green tea derivative epigallocatechin-3-gallate.

Source: J Urol. 200;170(3):773-6.

Author: Kemberling JK, Hampton JA, Keck RW, Gomez MA, Selman SH.

Affiliation: Department of Urology, Medical College of Ohio, 3065 Arlington Avenue, Dowling Hall 2170, Toledo, OH 43614-5807, USA.

Abstract: We evaluated the green tea derivative epigallocatechin-3-gallate (EGCG) as an intravesical agent for the prevention of transitional cell tumor implantation. In vitro studies were performed in the AY-27 rat transitional cell cancer and the L1210 mouse leukemia cell lines. Cells were exposed to increasing concentrations of EGCG for 30 minutes to 48 hours. Surviving cell colonies were then determined. The clonal assays showed a time dose related response to EGCG. Intravesical instillation of EGCG inhibits the growth of AY-27 rat transitional cells implanted in this model.

Chemoprevention of bladder cancer.

Source: Urol Clin North Am. 2002;29(1):157-68.

Author: Kamat AM, Lamm DL.

Affiliation: Department of Urology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.

Abstract: The data presented herein, although highly supportive for a protective role of various nutrients against bladder cancer, are far from definitive. Prospective randomized trials with a large sample size, longer follow-up, and an extended duration of treatment are needed to clarify the association between micronutrients and cancer protection. With these caveats in mind, several recommendations can be made. Simple measures, such as drinking more fluids (especially water), can have a profound impact on the incidence of bladder cancer. Vitamins are being extensively studied in chemopreventive trials for different cancers. There is strong evidence for a chemoprotective effect of vitamin A in bladder cancer. The authors recommend 32,000 IU/day of vitamin A initially, with lower doses (24,000 IU) for persons less than 50 kg. Because liver toxicity is a possibility with long-term administration, the dose should be decreased to 16,000 IU after 3 years. High doses of beta-carotene should be avoided based on a large clinical trial reporting a 25% increase in the number of cases of prostate cancer and a statistically significant increase in the incidence of lung cancer. Vitamin B6 has been studied in several clinical trials in bladder cancer. The US-based Veterans Administration cooperative study found benefit for vitamin B6 when given as a single agent. Data for vitamins C and E are insufficient to recommend either agent as stand-alone treatment. Nonetheless, each of these vitamins is known to have beneficial effects, including improved function of the immune system. It is possible that only a small percentage of patients with bladder cancer respond to vitamins B6, C, or E, yet each is safe, nontoxic, and inexpensive. In an effort to pool the efficacy of individual agents and to increase the power of study, the authors evaluated the combination of vitamins A, B6, C, and E in a double-blind trial. The observed 50% 5-year reduction in tumor recurrence was highly significant and greater than would be expected for any of the individual ingredients and suggests that combinations of nutritional agents may be most appropriate. A large-volume study along similar lines is being conducted. Among the numerous other compounds and dietary substances purported to have chemopreventive effect, soybeans, garlic, and green tea stand out as having the greatest promise and can freely be recommended to patients. For synthetically synthesized agents such as celecoxib, piroxicam, or DFMO, recommendations must be deferred until the results of clinical trials are conclusively in favor of their use. Many of the dietary factors found to be protective against bladder cancer are being investigated in other cancers and are beneficial to general health. Although naturally occurring nutrients are ideal, especially because the delicate balance of various micronutrients might be impossible to synthesize in the laboratory, the general population finds it easier to take vitamin supplements. Unfortunately, dietary changes such as decreasing fat and increasing fruit and vegetable intake are more difficult to initiate. There is a mistaken notion that simply because an agent is naturally occurring, it cannot be as beneficial as taking a substance synthesized in the laboratory. Even in a high-risk group such as nuclear-bomb survivors in Japan, high consumption of vegetables and fruit is protective against bladder cancer [44]. Encouraging patients to follow an essentially healthy food habit lifestyle will be a significant contribution in the fight against cancer.

Fruit and vegetable intakes are associated with lower risk of bladder cancer among women in the Multiethnic Cohort Study.

Source: http://www.ncbi.nlm.nih.gov/pubmed/23739308

Author: Park SY, Ollberding NJ, Woolcott CG, Wilkens LR, Henderson BE, Kolonel LN.

Affiliation: Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, USA.

Abstract: Fruits and vegetables have been examined for their possible effects on the risk of bladder cancer, as they contain numerous nutrients, phytochemicals, and antioxidants with potentially anticarcinogenic properties. In a prospective analysis of 185,885 older adults participating in the Multiethnic Cohort Study, the authors examined whether the consumption of fruits and vegetables, or of nutrients concentrated in fruits and vegetables, was associated with bladder cancer risk. A total of 581 invasive bladder cancer cases (429 men and 152 women) were diagnosed over a mean follow-up period of 12.5 y. In women, total fruits and vegetables, total vegetables, yellow-orange vegetables, total fruits, and citrus fruits were inversely associated with the risk of invasive bladder cancer in risk factor-adjusted models. In addition, women with the highest intakes of vitamins A, C, and E; the carotenoids á-carotene, â-carotene, and â-cryptoxanthin; and folate had a lower risk of bladder cancer. For men, no associations for fruits, vegetables, or nutrients were found overall, although inverse associations were observed for vegetable intake among current smokers, and in ethnic-specific analyses, for fruit and vegetable intake among Latinos specifically. Conclusion: The authors’ findings suggest that greater consumption of fruits and vegetables may lower the risk of invasive bladder cancer among women and highlight the need for specific subgroup analyses in future studies.

Breast Cancer

EPA and DHA Intakes from Marine Sources may be Associated with Improved Breast Cancer Prognosis

Source: J Nutr, 2011;141(2):201-206

Author: Patterson RE, Pierce JP, et al

Affiliation: Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA

Abstract: In a follow-up study involving 3,081 women who had been diagnosed and treated for early stage breast cancer, results indicate that dietary supplementation with marine fatty acids (EPA and DHA) may be associated with reduced risks of additional breast cancer events and all-cause mortality.

One-carbon metabolism and breast cancer: an epidemiological perspective.

Source: Journal of genetics and genomics 2009; 36(4):203-14.

Author: Xu X, Chen J.

Affiliation: Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, USA.

Abstract: One-carbon metabolism is a network of biological reactions that plays critical role in DNA methylation and DNA synthesis, and in turn, facilitates the cross-talk between genetic and epigenetic processes. Genetic polymorphisms and supplies of cofactors (e.g. folate, vitamins B) involved in this pathway have been shown to influence cancer risk and even survival. In this review, the authors summarized the epidemiological evidence for one-carbon metabolism, from both genetics and lifestyle aspects, in relation to breast cancer risk. They also discussed this pathway in relation to breast cancer survival and the modulation of one-carbon polymorphism in chemotherapy. Emerging evidence on modulation of DNA methylation by one-carbon metabolism suggests that disruption of epigenome might have been the underlying mechanism. More results are expected and will be translated to guidance to the general population for disease prevention as well as to clinicians for treatment and management of the disease.

Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial

Source: Breast cancer research and treatment 2011; 129(1):107-16

Author: Rastelli AL, Taylor ME, Gao F, Armamento-Villareal R, Jamalabadi-Majidi S, Napoli N, Ellis MJ

Affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, USA

Abstract: A double-blind placebo-controlled randomized phase II trial was performed to determine whether High Dose Vitamin D2 supplementation (HDD) in women receiving adjuvant Anastrozole* improves aromatase inhibitor-induced musculoskeletal symptoms (AIMSS) and bone loss. Patients with early breast cancer and AIMSS were stratified according to their baseline 25-hydroxy vitamin D (25OHD) level. Stratum A (20-29 ng/ml) received either HDD 50,000 IU capsules weekly for 8 weeks then monthly for 4 months or placebo. Stratum B (10-19 ng/ml) received either HDD for 16 weeks and then monthly for 2 months, or placebo. AIMSS was assessed by the Brief Pain Inventory-Short Form (BPI-SF), the Fibromyalgia Impact Questionnaire (FIQ), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) at baseline, 2, 4, and 6 months. Bone Mineral Density (BMD) was measured at baseline and at 6 months. The primary endpoint of the study was the change-from-baseline musculoskeletal pain. The secondary endpoint was the percent change in BMD at 6 months. Sixty women were enrolled. Baseline characteristics were comparable between the groups. At 2 months, FIQ pain, BPI worst-pain, BPI average-pain, BPI pain-severity, and BPI interference scores were better in the HDD than placebo group. The positive effect of HDD on AIMSS was stronger across all time points in Stratum B than Stratum A. BMD at the femoral neck decreased in the placebo and did not change in the HDD group. Weekly HDD improves AIMSS and may have a positive effect on bone health. Vitamin D supplementation strategies for breast cancer patients on AI should be further investigated.

* Anastrozole (INN) (marketed under the trade name Arimidex by AstraZeneca) is an aromatase-inhibiting drug approved for treatment of breast cancer after surgery, as well as for metastasis in both pre and post-menopausal women. The severity of breast cancer is increased by estrogen, as sex hormones cause hyperplasia, and differentiation at estrogen receptor sites. Anastrozole works by inhibiting the synthesis of estrogen.

Prospective Associations between Plasma Saturated, Monounsaturated and Polyunsaturated Fatty Acids and Overall and Breast Cancer Risk - Modulation by Antioxidants: A Nested Case-Control Study.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24587366

Author: Pouchieu C, et al.

Affiliation: Sorbonne Paris Cité, Nutritional Epidemiology Research Team (EREN), Epidemiology and Biostatistics Center, Inserm U1153, Inra U1125, Cnam, University Paris 13,

Abstract: Mechanistic data suggest that different types of fatty acids play a role in carcinogenesis and that antioxidants may modulate this relationship but epidemiologic evidence is lacking. The aim of this study was to investigate the association between plasma saturated, monounsaturated and polyunsaturated fatty acids (SFAs, MUFAs and PUFAs) and overall and breast cancer risk and to evaluate the potential modulatory effect of an antioxidant supplementation on these relationships. A nested case-control study included all first incident cancer cases diagnosed in the SU.VI.MAX study between 1994 and 2002 (n = 250 cases, one matched control/case). Participants to the SU.VI.MAX randomized controlled trial received either vitamin/mineral antioxidants or placebo during this intervention period. Baseline fatty acid composition of plasma total lipids was measured by gas chromatography. Conditional logistic regression was performed overall and stratified by intervention group. Dihomo-ã-linolenic acid, the dihomo-ã-linolenic/linoleic acids ratio, mead acid, and palmitoleic acid were inversely associated with overall cancer risk. The arachidonic/dihomo-ã-linolenic acids ratio and linoleic acid were directly associated with overall cancer risk. Similar results were observed for breast cancer specifically. In stratified analyses, associations were only observed in the placebo group. Notably, total PUFAs were directly associated with overall and breast cancer risk in the placebo group only. Specific SFAs, MUFAs and PUFAs were prospectively differentially associated with cancer risk. In addition, this study suggests that antioxidants may modulate these associations by counteracting the potential effects of these fatty acids on carcinogenesis.

Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: Systematic review and meta-analysis of prospective cohort studies.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24582912

Author: Maalmi H, et al.

Affiliation: German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany.

Abstract: The aim of this study was to estimate the association between serum 25-hydroxyvitamin D (25(OH)D) levels and survival among colorectal and breast cancer patients. The researchers performed a comprehensive literature search of prospective cohort studies assessing the association of serum 25(OH)D levels with survival in colorectal and breast cancer patients. Study characteristics and results were extracted and dose-response relationships were graphically displayed in a standardised manner. Meta-analyses using random effects models were performed to estimate pooled hazard ratios. The systematic search yielded five studies including 2330 colorectal cancer patients and five studies including 4413 breast cancer patients all of which compared mortality across two to five categories of 25(OH)D levels. Among colorectal cancer patients, pooled hazard ratios (95% confidence intervals) comparing highest with lowest categories were 0.71 and 0.65 for overall and disease-specific mortality, respectively. For breast cancer patients, the corresponding pooled estimates were 0.62 and 0.58, respectively. No significant evidence of heterogeneity between studies was observed. Conclusion: Higher 25(OH)D levels (>75nmol/L) were associated with significantly reduced mortality in patients with colorectal and breast cancer. Randomised controlled trials are needed to evaluate whether vitamin D supplementation can improve survival in colorectal and breast cancer patients with low vitamin D status (25(OH)D<50nmol/L) at diagnosis and before treatment.

Multivitamin and mineral use and breast cancer mortality in older women with invasive breast cancer in the women's health initiative.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24104882

Author: Wassertheil-Smoller S, McGinn AP, Budrys N, et al.

Affiliation: Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, USA

Abstract: Multivitamin use is common in the United States. It is not known whether multivitamins with minerals supplements (MVM) used by women already diagnosed with invasive breast cancer would affect their breast cancer mortality risk. To determine prospectively the effects of MVM use on breast cancer mortality in postmenopausal women diagnosed with invasive breast cancer, a prospective cohort study was conducted of 7,728 women aged 50-79 at enrollment in the women's health initiative (WHI) in 40 clinical sites across the United States diagnosed with incident invasive breast cancer during WHI and followed for a mean of 7.1 years after breast cancer diagnosis. Use of MVM supplements was assessed at WHI baseline visit and at visit closest to breast cancer diagnosis, obtained from vitamin pill bottles brought to clinic visit. Outcome was breast cancer mortality. Analyses using propensity to take MVM were done to adjust for potential differences in characteristics of MVM users versus non-users. At baseline, 37.8 % of women reported MVM use. After mean post-diagnosis follow-up of 7.1 ± 4.1 (SD) years, there were 518 (6.7 %) deaths from breast cancer. In adjusted analyses, breast cancer mortality was 30 % lower in MVM users as compared to non-users. This association was highly robust and persisted after multiple adjustments for potential confounding variables and in propensity score matched analysis. Postmenopausal women with invasive breast cancer using MVM had lower breast cancer mortality than non-users. Conclusion: The results suggest a possible role for daily MVM use in attenuating breast cancer mortality in women with invasive breast cancer but the findings require confirmation.

Green tea improves metabolic biomarkers, not weight or body composition: a pilot study in overweight breast cancer survivors.

Source: http://www.ncbi.nlm.nih.gov/pubmed/20807303

Author: Stendell-Hollis NR, Thomson CA, Thompson PA, Bea JW, Cussler EC, Hakim IA.

Affiliation: Department of Nutritional Sciences, University of Arizona, Tucson, USA.

Abstract: Overweight status after breast cancer treatment may increase a woman's risk for recurrent disease and/or early onset cardiovascular disease. Green tea has been proposed to promote weight loss and favourably modify glucose, insulin and blood lipids. This pilot study tested the effect of daily decaffeinated green tea consumption for 6 months on weight and body composition, select metabolic parameters and lipid profiles in overweight breast cancer survivors. The effect of daily decaffeinated green tea intake on weight, body composition and changes in resting metabolic rate, energy intake, glucose, insulin, homeostasis model assessment--insulin resistance (HOMA-IR) and lipids was evaluated in overweight breast cancer survivors. Participants (n = 54) were randomised to 960 mL of decaffeinated green or placebo tea daily for 6 months. Mean (SD) tea intake among study completers (n = 39) was 5952 (1176) mL week⁻¹ and was associated with a significant reduction in energy intake. Change in body weight of -1.2 kg (green tea) versus +0.2 kg (placebo) suggests a weight change effect, although this was not statistically significant. Decaffeinated green tea intake was associated with elevated high-density lipoprotein (HDL) levels and non-significant improvements in the HDL/LDL ratio and HOMA-IR. Conclusion: Intake of decaffeinated green tea for 6 months was associated with a slight reduction in body weight and improved HDL and glucose homeostasis in overweight breast cancer survivors.

Use of isoflavone supplements is associated with reduced postmenopausal breast cancer risk.

Source: http://www.ncbi.nlm.nih.gov/pubmed/22886851

Author: Boucher BA, Cotterchio M, Anderson LN, Kreiger N, Kirsh VA, Thompson LU.

Affiliation: Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada.

Abstract: Botanical supplements are widely used and contain diverse ingredients, including isoflavones. Food-based isoflavones have been associated with reduced breast cancer risk. However, no study has comprehensively evaluated supplements identified by isoflavone content and breast cancer risk. Associations between ever use of 28 isoflavone supplements and breast cancer risk in Ontario, Canada were evaluated using cases (n = 3,101) identified in 2002-2003 from the Ontario Cancer Registry and controls (n = 3,471) identified through random digit dialing methods. Multivariate logistic regression was used to estimate age-adjusted odds ratio (AOR) and 95% confidence intervals (CI). Several individual supplements were associated with reduced breast cancer risk. Use of any isoflavone supplements was associated with reduced risk when ¡Ý 3 were ever used or any was taken >5 years; high content supplements were consistently associated with reduced risk. Risk reduction was confined to postmenopausal breast cancer for both individual and combined supplements, and was strongest in the latter among high content users who ever took ¡Ý 3 supplements or any >5 years. Associations did not differ by estrogen-progesterone tumor receptor status. In conclusion, isoflavone supplements were associated with decreased postmenopausal breast cancer risk.

Simultaneous Inhibition of Cell-Cycle Proliferation Survival Metastatic Pathways and Intrduction of Apoptosis in Breast Cancer Cells by a Phytochemicak Super Cocktail Genes That Underpin Its Mode of Action

Source: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3842439

Author: Allal Ouhtit, Rajiv Lochan Gaur, Mohamed Abdraboh, et al

Affiliation: Stanley S Scott Cancer Center, Louisiana Health Sciences Center, New Orleans, Louisiana.

Abstract: Traditional chemotherapy and radiotherapy for cancer treatment face serious challenges such as drug resistance and toxic side effects. Complementary / Alternative medicine is increasingly being practiced worldwide due to its safety beneficial therapeutic effects. The authors hypothesized that a super combination (SC) of known phytochemicals used at bioavailable levels could induce 100% killing of breast cancer (BC) cells without toxic effects on normal cells and that microarray analysis would identify potential genes for targeted therapy of BC. Mesenchymal Stems cells (MSC, control) and two BC cell lines were treated with six well established pro-apoptotic phytochemicals individually and in combination (super cocktail), at bioavailable levels. The compounds were ineffective individually. In combination, they significantly suppressed BC cell proliferation (>80%), inhibited migration and invasion, caused cell cycle arrest and induced apoptosis resulting in 100% cell death. However, there were no deleterious effects on MSC cells used as control. Furthermore, the SC down-regulated the expression of PCNA, Rb, CDK4, BcL-2, SVV, and CD44 (metastasis inducing stem cell factor) in the BC cell lines. Microarray analysis revealed several differentially expressed key genes (PCNA, Rb, CDK4, Bcl-2, SVV, P53 and CD44) underpinning SC-promoted BC cell death and motility. Four unique genes were highly up-regulated (ARC, GADD45B, MYLIP and CDKN1C). This investigation indicates the potential for development of a highly effective phytochemical combination for breast cancer chemoprevention / chemotherapy. The novel over-expressed genes hold the potential for development as markers to follow efficacy of therapy.

Levels of serum 25-hydroxy-vitamin D in benign and malignant breast masses.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24528013

Author: Alipour S, et al.

Affiliation: Department of Surgery, Arash Women's Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Abstract: The researchers compared serum 25-hydroxy-vitamin D levels in women with benign and malignant breast masses and controls. Levels of vitamin D were measured by electrochemiluminescense. Serum levels >35 ng/ml, 25-35 ng/ml, 12.5-25 ng/ml and <12.5 ng/ml were considered as normal, mild, moderate and severe vitamin D deficiency, respectively. Overall, 364 women were included in the control, 172 in the benign and 136 in the malignant groups. The median serum vitamin D level was significantly lower in breast cancers than controls. Levels were also lower in malignant than benign cases and in benign cases than controls although statistically non-significant. Concluding, multinomial logistic regression analysis showed that severe vitamin D deficiency causes a three-fold increase in the risk of breast cancer while this was not the case for moderate and mild deficiency.

Breast Cancer, calcium and multivitamins

Source: http://www.ncbi.nlm.nih.gov/pubmed/24817834

Author: Vergne Y, et al.

Affiliation: Student in the Public Health Program, Ponce School of Medicine and Health Sciences, Ponce, Puerto Rico

Abstract: Over recent decades, considerable interest has emerged regarding whether vitamins and/or other supplements can lower the risk of breast cancer (BC). However, previous epidemiologic studies that investigated the association between intake of multivitamin and supplements of single vitamins and minerals and BC risk have reported conflicting results. This study examined whether multivitamin and calcium use was associated with BC incidence and DNA repair capacity (DRC). The research team designed an observational, case-control study. All work was performed at the Ponce School of Medicine and Health Sciences under the direct supervision of principal investigator Dr Jaime Matta. Participants were 836 women recruited primarily from the private practices of oncologists, gynaecologists, and surgeons in Puerto Rico. A total of 312 individuals in the breast cancer (BC) group and 524 individuals in the control group were compared for their multivitamin and calcium intake, DRC levels, and other covariates. Odds ratios (OR) were used as measures of association between BC and DRC and other selected variables. The BC group had 30% reduced odds of taking multivitamins and calcium as compared to controls. Women with low DRC had 50% lower odds of taking calcium and 30% lower odds of currently taking vitamins. Although this study is a case-control study in which the risk of BC could not be assessed, results suggest that vitamin supplementation could be an independent protective factor for BC. Calcium intake appears to affect DRC in a positive way, because it was associated with a high DRC level, which in turn is associated with low odds for BC.

Microbial dysbiosis is associated with human breast cancer.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24421902

Author: Xuan C, et al.

Affiliation: Dirks/Dougherty Laboratory for Cancer Research, Department of Translational Immunology, John Wayne Cancer Institute, Santa Monica, California, United States of America.

Abstract: Breast cancer affects one in eight women in their lifetime. Though diet, age and genetic predisposition are established risk factors, the majority of breast cancers have unknown etiology. The human microbiota refers to the collection of microbes inhabiting the human body. Imbalance in microbial communities, or microbial dysbiosis, has been implicated in various human diseases including obesity, diabetes, and colon cancer. Therefore, the researchers investigated the potential role of microbiota in breast cancer by next-generation sequencing using breast tumor tissue and paired normal adjacent tissue from the same patient. In a qualitative survey of the breast microbiota DNA, the researchers found that the bacterium Methylobacterium radiotolerans is relatively enriched in tumor tissue, while the bacterium Sphingomonas yanoikuyae is relatively enriched in paired normal tissue. The relative abundances of these two bacterial species were inversely correlated in paired normal breast tissue but not in tumor tissue, indicating that dysbiosis is associated with breast cancer. Furthermore, the total bacterial DNA load was reduced in tumor versus paired normal and healthy breast tissue as determined by quantitative PCR. Interestingly, bacterial DNA load correlated inversely with advanced disease, a finding that could have broad implications in diagnosis and staging of breast cancer. Lastly, the reserachers observed lower basal levels of antibacterial response gene expression in tumor versus healthy breast tissue. Taken together, these data indicate that microbial DNA is present in the breast and that bacteria or their components may influence the local immune microenvironment. These findings suggest a previously unrecognized link between dysbiosis and breast cancer which has potential diagnostic and therapeutic implications.

Cancer and green tea

Anti-carcinogenic effects of EGCG against estrogen-negative breast cancer cells

Epigallocatechin-3-Gallate Induces Apoptosis in Estrogen Receptor-Negative Human Breast Carcinoma Cells via Modulation in protein Expression of p53 and Bax and Caspase-3 Activation

Source: Mol Cancer Ther. 2005 Jan;4(1):81-90

Author: Roy AM, Baliga MS, Katiyar SK.

Affiliation: Department of Dermatology, University of Alabama at Birmingham, 1670, University Boulevard, Volker Hall 557, P.O. Box 202, Birmingham, AL 35294, USA

Abstract: Using the MDA-MB-468 human breast cancer cell line as an in vitro model of ER-negative breast cancers, this study found that treatment of EGCG resulted in dose-dependent (5-80 microg/mL) and time-dependent (24-72 hours) inhibition of cellular proliferation (15-100%) and cell viability (3-78%) in MDA-MB-468 cells. Decrease in cell viability was associated with the induction of apoptosis (18-66%) which was analyzed by DNA ladder assay, fluorescence staining, and flow cytometry. The results of this study provide evidence that EGCG possesses anticarcinogenic effect against ER-negative breast cancer cells and thus provide the molecular basis for the future development of EGCG as a novel and pharmacologically safe chemopreventive agent for breast cancer prevention.

Anti-inflammatory mechanism of green tea polyphenols

Green Tea Polyphenols Block Endotoxin-Induced Tumor Necrosis Factor-Production and Lethality in a Murine Model

Source: J Nutr. 1998 Dec;128(12):2334-40.

Author: Yang F, de Villiers WJ, McClain CJ, Varilek GW.

Affiliation: Graduate Program in Nutritional Sciences, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.

Abstract: This study analysis the role of green tea polyphenols in inflammations showing that tumor necrosis factor-alpha(TNFalpha) plays a pivotal role. The study postulates that green tea polyphenols regulate TNFalpha gene expression by modulating NF-KB activation through their antioxidant properties. In the macrophage cell line, RAW264.7, (-)epigallocatechin gallate (EGCG), the major green tea polyphenol, decreased lipopolysaccharide (LPS)-induced TNFalpha production in a dose-dependent fashion (50% inhibition at 100 mmol/L). EGCG also inhibited LPS-induced TNFalpha mRNA expression and nuclear NF-KB-binding activity in RAW264.7 cells (30-40% inhibition at 100 mmol/L). Similarly, EGCG inhibited LPS-induced TNFalpha production in elicited mouse peritoneal macrophages. In male BALB/c mice, green tea polyphenols (given by oral gavage 2 h prior to an i.p. injection of 40 mg LPS/kg body wt) decreased LPS-induced TNFalpha production in serum in a dose-responsive fashion. The study concludes that the anti-inflammatory mechanism of green tea polyphenols is mediated at least in part through down-regulation of TNFalpha gene expression by blocking NF-KB activation.

Cellular and molecular effects of EGCG and green tea colon cancer

Epigallocatechin gallate and polyphenon E inhibit growth and activation of the epidermal growth factor receptor and human epidermal growth factor receptor-2 signaling pathways in human colon cancer cells.

Source: Clin Cancer Res. 2005 Apr 1;11(7):2735-46.

Author: Shimizu M, Deguchi A, Lim JT, Moriwaki H, Kopelovich L, Weinstein IB.

Affiliation: Herbert Irving Comprehensive Cancer Center and Department of Medicine, Columbia University Medical Center, New York, New York 10032-2704, USA.

Abstract: This study compared the cellular and molecular effects of EGCG with a well-standardized decaffeinated green tea catechin mixture Polyphenon E (Poly E) on human colon cancer cell lines. Both EGCG and Poly E preferentially inhibited growth of the Caco2, HCT116, HT29, SW480, and SW837 colon cancer cells when compared with the FHC normal human fetal colon cell line. The EGFR and HER2 proteins were overexpressed and constitutively activated in all of the colon cancer cell lines when compared with the FHC cell line. Treatment of HT29 cells with EGCG or Poly E caused an increase of cells in G1 and induced apoptosis. Both EGCG and Poly E caused a decrease in the phosphorylated forms of EGFR and HER2 proteins, and subsequently caused a decrease in the phosphorylated forms of the extracellular signal-regulated kinase and Akt proteins. The findings suggest that EGCG or Poly E may be useful in the chemoprevention and/or treatment of colon cancer. Poly E contains about 60% EGCG, yet pure EGCG and Poly E had similar potencies (expressed as microg/ml). Poly E may be preferable because it is easier to prepare and this mixture of catechins may exert synergistic effects.

Clinical and in vitro evidence of anti-cancer effects of green tea and EGCG

Green Tea and Cancer Chemoprevention

Source: Mutat Res. 1999 Jul 16;428(1-2):339-44

Author: Suganuma M, Okabe S, Sueoka N, Sueoka E, Matsuyama S, Imai K, Nakachi K, Fujiki H.

Affiliation: Saitama Cancer Center Research Institute, Ina, Kitaadachi-gun, Saitama 362-0806, Japan.

Abstract: This study demonstrates that epicatechin (EC) enhanced incorporation of 3H-EGCG into human lung cancer cell line PC-9 cells. EC along with another cancer preventive agent sulindac also synergistically enhanced apoptosis in PC-9 cells induced by epigallocatechin gallate  (EGCG). A case-control study on breast cancer patients revealed that high daily consumption of green tea was associated with a lower recurrence rate among Stages I and II patients. All the results suggest that consumption of green tea is a practical and effective cancer preventive both before cancer onset and after cancer treatment.

EGCG and Breast Cancer – in vitro and in vivo effects

Green Tea Polyphenols and its Constituent Epigallocatechin Gallate Inhibits Proliferation of Human Breast Cancer Cells in Vitro and in Vivo

Source: Cancer Lett. 2007 Jan 8;245(1-2):232-41. Epub 2006, Mar 6

Author: Thangapazham RL, Singh AK, Sharma A, Warren J, Gaddipati JP, Maheshwari RK.

Affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.

Abstract: Several epidemiological studies have shown that breast cancer progression is delayed in the Asian population that consumes green tea on regular basis. This study reports the effectiveness of green tea polyphenols (GTP) and its constituent Epigallocatechin Gallate (EGCG) in tumor regression using both in-vitro cell culture models and in vivo athymic nude mice models of breast cancer. The results suggest that GTP and EGCG treatment inhibits proliferation and induce apoptosis of MDA-MB-231 cells in-vitro and in-vivo, and sustain contention that GTP and EGCG have anti-tumor properties.

Green Tea Polyphenol and Epigallocatechin Gallate Induce Apoptosis and Inhibit Invasion in Human Breast Cancer Cells.

Source: Cancer Biol Ther. 2007 Dec;6(12):1938-43.

Author: Thangapazham RL, Passi N, Maheshwari RK.

Affiliation: Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.

Abstract: This study have evaluated apoptotic and anti-invasive activity of green tea polyphenols (GTP) and its principal constituent Epigallocatechin gallate (EGCG) in MDA-MB-231 human breast cancer cell line. In in vitro human breast cancer model, EGCG and GTP induced apoptosis and significantly decreased invasion of breast cancer cells. Quantitative fluorescence labeling resulted in a 24-28% reduction in invasion through matrigel by EGCG and 15-23% reduction by GTP in a dose dependent manner. Focussed microarray analysis and reverse transcriptase polymerase chain reaction and zymogram analysis revealed inhibition of MMP-9 expression by polyphenol treatment. Furthermore, AKT was found to be inhibited both at the RNA and protein level by polyphenol treatment. Moreover EGCG and GTP decreased AKT phosphorylation as found out by Western blotting for Phospho-AKT (Ser-473). beta-catenin level was found to be decreased both in cytoplasm and nucleus. For the first time the study reports the connection of beta-catenin and AKT modulation by GTP and EGCG as a possible mechanism for the induction of apoptosis in human breast cancer cells and also inhibition in their invasive capacity.

EGCG effects on VEGF production in various cancer cell lines

Epigallocatechin-3-Gallate Decreases VEGF Production in Head and Neck and Breast Carcinoma Cells by Inhibiting EGFR-Related Pathways of Signal Transduction

Source: J Exp Ther Oncol. 2002 Nov-Dec;2(6):350-9.

Author: Masuda M, Suzui M, Lim JT, Deguchi A, Soh JW, Weinstein IB.

Affiliation: Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, HHSC-1509, 701 W. 168th Street, New York, NY 10032, USA.

Abstract: This study found that epigallocatechin-3-gallate (EGCG), a major biologically active component of green tea, inhibited activation of the epidermal growth factor receptor (EGFR) and related signaling pathways in head and neck squamous cell carcinoma (HNSCC) cells. Treatment with EGCG inhibited the constitutive activation of the EGFR, Stat3, and Akt in both cell lines. These changes were associated with inhibition of VEGF promoter activity and cellular production of VEGF. The obtained results suggest that EGCG inhibits VEGF production by inhibiting both the constitutive activation of Stat3 and NF-kappa B, but not extracellular-signal-regulated kinase (ERK) or Akt, in these cells. Therefore, EGCG may be useful in treating HNSCC and breast carcinoma because it can exert both antiproliferative and antiangiogenic activities.

EGCG potential as a pro-apoptotic agent

Cell Cycle Dysregulation by Green Tea Polyphenol Epigallocatechin-3-Gallate.

Source: Biochem Biophys Res Commun. 2000 Aug 28;275(2):328-34

Author: Ahmad N, Cheng P, Mukhtar H.

Affiliation: Department of Dermatology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, Ohio 44106, USA.

Abstract: This study, employing A431 cells, provides evidence for the involvement of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery during cell cycle deregulation by EGCG. The study suggests that EGCG causes an induction of G1-phase ckis, which inhibit the cyclin-cdk complexes operative in G0/G1 phase of the cell cycle thereby causing a G0/G1-phase arrest of the cell cycle, which is irreversible process ultimately resulting in an apoptotic cell death. The study suggests that the naturally occurring agents such as green tea polyphenols which may inhibit cell cycle progression could be developed as potent anticancer agents for the management of cancer.

Growth Inhibitory and Antimetastatic Effect of Green Tea polyphenols in vitro and in vivo

Growth Inhibitory and Antimetastatic Effect of Green Tea polyphenols on Metastasis-Specific Mouse Mammary Carcinoma 4T1 Cells In Vitro and In Vivo Systems

Source: Clin Cancer Res. 2005 Mar 1;11(5):1918-27

Author: Baliga MS, Meleth S, Katiyar SK.

Affiliation: Department of Dermatology, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 35294, USA.

Abstract: This study examined the effect of green tea polyphenols (GTP) on growth and metastasis of highly metastatic mouse mammary carcinoma 4T1 cells in vitro and in vivo systems. 4T1 cells were treated with (-)-epigallocatechin-3-gallate (EGCG), and the effect was determined on cellular proliferation, induction of apoptosis, proapoptosis, and antiapoptotic proteins of Bcl-2 family, and caspase 3 and poly(ADP-ribose) polymerase activation following 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, and Western blot analysis. This study suggests that GTP have the ability to prevent the development of breast cancer and its metastasis; however, further in vivo studies are required to identify the molecular targets.

Growth inhibitory effect of EGCG on human breast cancer cells

Inhibition of Cyclin-Dependent Kinases 2 and 4 Activities as well as Induction of Cdk Inhibitors p21 and p27 During Growth Arrest of Human Breast Carcinoma Cells by (-)-Epigallocatechin-3-Gallate.

Source: J Cell Biochem. 1999 Oct 1;75(1):1-12

Author: Liang YC, Lin-Shiau SY, Chen CF, Lin JK.

Affiliation: Institute of Biochemistry, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.

Abstract: This study investigated the effects of EGCG and other catechins on the cell cycle progression. DNA flow cytometric analysis indicated that 30 microM of EGCG blocked cell cycle progression at G1 phase in asynchronous MCF-7 cells. In addition, cells exposed to 30 microM of EGCG remained in the G1 phase after release from aphidicolin block. Over a 24-h exposure to EGCG, the Rb protein changed from hyper- to hypophosphorylated form and G1 arrest developed. The results suggest that EGCG either exerts its growth-inhibitory effects through modulation of the activities of several key G1 regulatory proteins such as Cdk2 and Cdk4 or mediates the induction of Cdk inhibitor p21 and p27.

Herbal medicine in cancer prevention

New TNF-Alpha Releasing Inhibitors as Cancer Preventive Agents from Traditional Herbal Medicine and combination Cancer prevention Study with EGCG and Sulindac or Tamoxifen.

Source: Mutat Res. 2003 Feb-Mar;523-524:119-25.

Author: Fujiki H, Suganuma M, Kurusu M, Okabe S, Imayoshi Y, Taniguchi S, Yoshida T.

Affiliation: Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-Cho, Tokushima 770-8514, Japan. hfujiki@ph.bunri-u.ac.jp

Abstract: This study review two important results with EGCG: the synergistic effects of EGCG with sulindac or tamoxifen on cancer preventive activity in PC-9 cells, and cancer prevention of intestinal tumor development in multiple intestinal neoplasia (Min) mice by co-treatment using EGCG with sulindac. The study reports new findings on additional gene expression resulting from co-treatment with EGCG and sulindac in PC-9 cells compared with gene expression by EGCG alone or sulindac alone. The results indicate that, with the continuing spread of cancer chemoprevention as a fundamental medical strategy, both clinicians and researchers should take a closer look at herbal medicine.

Investigation of various cellular anti- cancer mechanisms of tea polyphenols

Mechanisms of Cancer Prevention by Green and Black Tea Polyphenols

Source: Anticancer Agents Med Chem. 2006 Sep;6(5):389-406

Author: Beltz LA, Bayer DK, Moss AL, Simet IM.

Affiliation: Department of Biology, University of Northern Iowa, Cedar Falls, IA 50614, USA. lisa.beltz@uni.edu

Abstract: This study delineates the wide range of mechanisms by which epigallocatechin gallate (ECGC) and other green and black tea polyphenols inhibit cancer cell survival. EGCG suppressed androgen receptor expression and signalling via several growth factor receptors. Polyphenols reduced angiogenesis in part by decreasing vascular endothelial growth factor production and receptor phosphorylation. Recent work demonstrated that EGCG reduced dihydrofolate reductase activity, which would affect nucleic acid and protein synthesis. It also acted as an aryl hydrocarbon receptor antagonist by directly binding the receptor's molecular chaperone, heat shock protein 90. In conclusion, green and black tea polyphenols act at numerous points regulating cancer cell growth, survival, and metastasis, including effects at the DNA, RNA, and protein levels.

Molecular basis of EGCG effects in breast cancer cells

Tea polyphenol (-)-Epigallocatechin 3-Gallate Suppresses Heregulin-Beta1-Induced Fatty Acid Synthase Expression in Human Breast Cancer Cells by Inhibiting Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase Cascade Signaling

Source: J Agric Food Chem. 2007 Jun 27;55(13):5030-7.

Author: Pan MH, Lin CC, Lin JK, Chen WJ.

Affiliation: Department of Seafood Science, National Kaohsiung Marine University, No. 142, Hai-Chuan Road, Nan-Tzu, Kaohsiung 811, Taiwan.

Abstract: This study examined the effects of EGCG on FAS expression modulated by another member of the erbB family, that is, HER2 or HER3. It identified that heregulin-beta1 (HRG-beta1), a HER3 ligand, stimulated dose-dependent FAS expression in breast cancer cell lines MCF-7 and AU565, but not MDA-MB-453. The time-dependent increase in FAS expression after HRG-beta1 stimulation was also observed in MCF-7 cells, and this up-regulation was de novo RNA synthesis dependent. The results indicate that EGCG may be useful in the chemoprevention of breast carcinoma in which FAS overexpression results from HER2 or/and HER3 signaling.

Multiple mechanistic aspects of anti-caner effects of green tea and epidemiological evidence

Cancer Prevention with Green Tea and Monitoring by a New Biomarker, hnRNP B1.

Source: Mutat Res. 2001 Sep 1;480-481:299-304

Author: Fujiki H, Suganuma M, Okabe S, Sueoka E, Sueoka N, Fujimoto N, Goto Y, Matsuyama S, Imai K, Nakachi K.

Affiliation: Saitama Cancer Center, Ina, Kitaadachi-gun, Saitama 362-0806, Japan. hfujiki@cancer-c.pref.saitama.jp

Abstract: This study briefly reviews four topics related to mechanisms of action of tea polyphenols: (I) identification of the genes commonly affected by EGCG, as demonstrated by Clontech's Atlas cDNA Expression Array; (II) the significance of heterogeneous nuclear ribonucleoprotein B1 (hnRNP B1) as a new biomarker for early detection of lung cancer, and inhibition of its expression by EGCG; (III) the synergistic or additive effects of EGCG with the cancer preventive agents, sulindac and tamoxifen, on induction of apoptosis in PC-9 cells and on inhibition of intestinal tumor development in multiple intestinal neoplasia (Min) mice; (IV) the results of a 10 year prospective cohort study demonstrating the effectiveness of daily consumption of green tea in preventing cancer, and a prototype study for developing green tea beverage as cancer preventive.

Novel molecular mechanism involved in inhibition of invasiveness of breast cancer cells

Activation of FOXO3a by the Green Tea Polyphenol Epigallocatechin-3-Gallate Induces Estrogen Receptor Alpha Expression Reversing Invasive phenotype of Breast Cancer Cells.

Source: Cancer Res. 2007 Jun 15;67(12):5763-70

Author: Belguise K, Guo S, Sonenshein GE.

Affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Abstract: This study shows that EGCG treatment of Her-2/neu-driven mammary tumor cells alters the expression of key regulators in the epithelial to mesenchymal transition (EMT) pathway, reducing invasive phenotype. Specifically, the epithelial genes E-cadherin, gamma-catenin, MTA3, and estrogen receptor alpha (ERalpha) were up-regulated by EGCG, whereas the proinvasive snail gene was down-regulated. Consistently, EGCG inhibited branching colony growth and invasion in Matrigel. EGCG treatment similarly inhibited invasive phenotype of mouse mammary tumor cells driven by Nuclear Factor-kappaB c-Rel and protein kinase CK2, frequently found overexpressed in human breast disease. This study also identifies, for the first time, a role for FOXO3a in the inhibition of invasive phenotype in breast cancer cells with active ERalpha signaling and elucidate a novel mechanism whereby EGCG represses EMT of breast cancer cells.

Review on EGCG role in cancer

Reading the Tea Leaves: Anticarcinogenic Properties of (-)-Epigallocatechin-3-Gallate.

Source: Mayo Clin Proc. 2007 Jun;82(6):725-32.

Author: Carlson JR, Bauer BA, Vincent A, Limburg PJ, Wilson T.

Affiliation: Department of Biology, Winona State University, Winona, MN 55987, USA.

Abstract: This study that is based on a comprehensive search of the PubMed database and other secondary data sources indicates that EGCG functions as an antioxidant, preventing oxidative damage in healthy cells, but also as an antiangiogenic agent, preventing tumors from developing a blood supply needed to grow larger. Furthermore, EGCG may stimulate apoptosis in cancerous cells by negatively regulating the cell cycle to prevent continued division. Finally, EGCG exhibits antibacterial activity, which may be implicated in the prevention of gastric cancer. Although in vitro research of the anticarcinogenic properties of EGCG seems promising, many diverse and unknown factors may influence its in vivo activity in animal and human models. Some epidemiological studies suggest that green tea compounds could protect against cancer, but existing data are inconsistent. Several clinical trials with green tea derivatives are ongoing, and further research should help to clarify the clinical potential of EGCG for chemoprevention and/or chemotherapy applications.

Role of tea polyphenols in regulating various molecular mechanisms associated with cancer

Potential Molecular Targets of Tea Polyphenols in Human Tumor Cells: Significance in Cancer Prevention

Source: In Vivo. 2002 Nov-Dec;16(6):397-403

Author: Kazi A, Smith DM, Daniel K, Zhong S, Gupta P, Bosley ME, Dou QP.

Affiliation: Drug Discovery Program, H. Lee Moffitt Cancer Center & Research Institute, Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, College of Medicine, University of South Florida, Tampa, FL 33612, USA.

Abstract: The most abundant and popular compound studied in tea research is (-)-epigallocatechin-3-gallate (EGCG), which acts as a powerful antioxidant and can inhibit a number of tumor cell proliferation- and survival-related proteins. Epidemiological studies have shown decreased cancer occurrence in individuals who drink green tea regularly. This study explains that role of tea polyphenols which inhibit the activities of many tumor-associated protein kinases, including epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, mitogen-activated protein kinase, and IkB kinase. Tea polyphenols have also been found to inhibit some cancer-related proteins that regulate DNA replication and transformation. This study suggests that by understanding the in vivo concentrations of tea polyphenols required to inhibit each of these activities, we may start to sort out in the future the mechanisms responsible for the cancer-preventive effects of tea.

Cancer and Quercetin

Multitargeted cancer prevention by quercetin.

Source: Cancer Lett. 2008;269(2):315-25.

Author: Murakami A, Ashida H, Terao J.

Affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.

Abstract: Quercetin is an anti-oxidative flavonoid widely distributed in the plant kingdom. Phenolic hydroxyl groups at the B-ring and the 3-position are responsible for its free radical-scavenging activity. Quercetin is commonly present as a glycoside and is converted to glucuronide/sulfate conjugates during intestinal absorption and only conjugated metabolites are therefore found in circulating blood. Although metabolic conversion attenuates its biological effects, active aglycone may be generated from the glucuronide conjugates by enhanced beta-glucuronidase activity during inflammation. With respect to its relationship with molecular targets relevant to cancer prevention, quercetin aglycone has been shown to interact with some receptors, particularly an aryl hydrocarbon receptor, which is involved in the development of cancers induced by certain chemicals. Quercetin aglycone has also been shown to modulate several signal transduction pathways involving MEK/ERK and Nrf2/keap1, which are associated with the processes of inflammation and carcinogenesis. Rodent studies have demonstrated that dietary administration of this flavonol prevents chemically induced carcinogenesis, especially in the colon, whilst epidemiological studies have indicated that an intake of quercetin may be associated with the prevention of lung cancer. Dietary quercetin is, therefore, a promising agent for cancer prevention and further research is warranted.

Quercetin Induces Tumor-Selective Apoptosis through Downregulation of Mcl-1 and Activation of Bax

Source: Clin Cancer Res 2010; 16(23):5679-91

Author: Senping Cheng, Ning Gao, Zhuo Zhang, Gang Chen, Amit Budhraja, Zunji Ke, Young-ok Son, Xin Wang, Jia Luo, and Xianglin Shi

Affiliation: Graduate Center for Toxicology and Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky

Abstract: To investigate the in vivo antitumor efficacy of quercetin in U937 xenografts and the functional roles of Mcl-1 and Bax in quercetin-induced apoptosis in human leukemia. Leukemia cells were treated with quercetin, after which apoptosis, Mcl-1 expression, and Bax activation and translocation were evaluated. The efficacy of quercetin as well as Mcl-1 expression and Bax activation were investigated in xenografts of U937 cells. The results suggest that quercetin may be useful for the treatment of leukemia by preferentially inducing apoptosis in leukemia versus normal hematopoietic cells through a process involving Mcl-1 downregulation, which, in turn, potentiates Bax activation and mitochondrial translocation, culminating in apoptosis.

Dietary quercetin, quercetin-gene interaction, metabolic gene expression in lung tissue and lung cancer risk

Source: Carcinogenesis 2010; 31 (4): 634-642.

Author: Tram Kim Lam, Melissa Rotunno, Jay H. Lubin, Sholom Wacholder, Dario Consonni, Angela C. Pesatori, Pier Alberto Bertazzi, Stephen J. Chanock, Laurie Burdette, et al

Affiliation: Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA, EPOCA, Epidemiology Research Center, Universita' degli Studi di Milano, Milan, Italy, Unit of Epidemiology, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy

Abstract: Epidemiological and mechanistic evidence on the association of quercetin-rich food intake with lung cancer risk and carcinogenesis are inconclusive. We investigated the role of dietary quercetin and the interaction between quercetin and P450 and glutathione S-transferase (GST) polymorphisms on lung cancer risk in 1822 incident lung cancer cases and 1991 frequency-matched controls from the Environment And Genetics in Lung cancer Etiology study. In conclusion, we observed an inverse association of quercetin-rich food with lung cancer risk and identified a possible mechanism of quercetin-related changes in the expression of genes involved in the metabolism of tobacco carcinogens in humans. Our findings suggest an interplay between quercetin intake, tobacco smoking, and lung cancer risk. Further research on this relationship is warranted.

Polyphenols as cancer chemopreventive agents

Source: J Cell Biochem Suppl. 1995; 59(22): 169-180

Author: Gary D. Stoner PhD, Hasan Mukhtar PhD

Affiliation: Department of Preventive Medicine, Ohio State University, Columbus, OH 43210, USA

Abstract: This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (-)-epigallocatechin-3-gallate (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation- and TPA-induced epidermal ornithine decarboxylase (ODC) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication. Curcumin is the yellow coloring agent in the spice tumeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition, curcumin inhibits TPA-induced skin tumor promotion in mice. The mechanisms for the anticarcinogenic effects of curcumin are similar to those of the GTPs. Curcumin enhances glutathione content and glutathione-S-transferase activity in liver; and it inhibits lipid peroxidation and arachidonic acid metabolism in mouse skin, protein kinase C activity in TPA-treated NIH 3T3 cells, chemically induced ODC and tyrosine protein kinase activities in rat colon, and 8-hydroxyguanosine formation in mouse fibroblasts. Ellagic acid is a polyphenol found abundantly in various fruits, nuts and vegetables. Ellagic acid is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and esophagus of rodents, and TPA-induced tumor promotion in mouse skin.

Cancer and Selenium

Selenium or No Selenium- That Is the Question in Tumor Patients: A New Controversy

Source: Integr Cancer Ther 2010; 9(2): 136-141

Author: Ralph Muecke, MD, Lutz Schomburg, PhD, Jens Buentzel, MD, Klaus Kisters, MD, Oliver Micke, MD

Affiliation: Lippe Hospital, Lemgo, Germany, Charité Berlin, Berlin, Germany, Suedharz Hospital, Nordhausen, Germany, St Anna Hospital, Herne, Germany, Franziskus Hospital, Bielefeld, Germany

Abstract: The essential trace element selenium, which is a crucial cofactor in the most important endogenous antioxidative systems of the human body, is attracting more attention from both laypersons and expert groups. The interest of oncologists mainly focuses on the following clinical aspects: protection of normal tissues, sensitizing in malignant tumors, antiedematous effect, prognostic impact of selenium, and effects in primary and secondary cancer prevention. Selenium is a constituent of the small group of selenocysteine-containing selenoproteins and elicits important structural and enzymatic functions. Selenium deficiency has been linked to increased infection risk and adverse mood states. It has been shown to possess cancer-preventive and cytoprotective activities in both animal models and humans. It is well established that it has a key role in redox regulation and antioxidant function, and hence in membrane integrity, energy metabolism, and protection against DNA damage. Recent clinical trials have shown the importance of selenium in clinical oncology. In 2009, a significant benefit of sodium selenite supplementation--with no protection of tumor cells, which is often suspected by oncologists-- was shown in a prospective randomized trial in gynecologic cancer patients undergoing radiation therapy. More recently, concerns arose from 2 large clinical prevention trials (NPC, SELECT) that selenium may increase the risk of developing type 2 diabetes. Despite obvious flaws in both studies and good counterarguments, controversy remains on the possible advantages and risks of selenium in cancer prevention. However, in the light of the recent clinical trials the potential benefits of selenium supplementation in tumor patients are becoming obvious, even though further research is needed.

Colorectal Cancer

Vitamin B6 and risk of colorectal cancer: a meta-analysis of prospective studies.

Source: JAMA. 2010; 303(11):1077-83.

Author: Larsson SC, Orsini N, Wolk A.

Affiliation: Division of Nutritional Epidemiology, National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Abstract: Mounting evidence indicates that vitamin B(6), a coenzyme involved in nearly 100 enzymatic reactions, may reduce the risk of colorectal cancer. The objective was to conduct a systematic review with meta-analysis of prospective studies assessing the association of vitamin B(6) intake or blood levels of pyridoxal 5'-phosphate (PLP; the active form of vitamin B(6)) with risk of colorectal cancer. Therefore relevant studies were identified by a search of MEDLINE and EMBASE databases to February 2010, with no restrictions. The authors also reviewed reference lists from retrieved articles. They included prospective studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the association between vitamin B(6) intake or blood PLP levels and the risk of colorectal, colon, or rectal cancer. Two authors independently extracted data and assessed study quality. Nine studies on vitamin B(6) intake and 4 studies on blood PLP levels were included in the meta-analysis. The risk of colorectal cancer decreased by 49% for every 100-pmol/mL increase in blood PLP levels. Conclusion: Vitamin B(6) intake and blood PLP levels were inversely associated with the risk of colorectal cancer in this meta-analysis.

EGCG and Lung Cancer

Synergistic Effects of (--)-Epigallocatechin gallate with (--)-Epicatechin, Sulindac, or Tamoxifen on Cancer-Preventive Activity in the Human Lung Cancer Cell Line PC-9.

Source: Cancer Res. 1999 Jan 1;59(1):44-7

Author: Suganuma M, Okabe S, Kai Y, Sueoka N, Sueoka E, Fujiki H.

Affiliation: Saitama Cancer Center Research Institute, Japan.

Abstract: This study shows that incorporation of [3H](-)-epigallocatechin gallate (EGCG) into human lung cancer cell line PC-9 can be significantly enhanced by (-)-epicatechin, an inert tea polyphenol without a galloyl moiety. (-)-Epicatechin enhanced apoptosis, growth inhibition of PC-9 cells, and inhibition of tumor necrosis factor-alpha release from BALB/c-3T3 cells by EGCG and other tea polyphenols with a galloyl moiety in a dose-dependent manner. This paper reports that whole green tea is a more effective mixture of tea polyphenols for cancer prevention in humans than EGCG alone and that it is even more effective when it is used in combination with other cancer preventives.

EGCG and Melanoma

Anti-Proliferative and Pro-apoptotic Effects of (-)-Epigallocatechin-3-Gallate on Human Melanoma: Possible Implications for the Chemoprevention of Melanoma

Source: Int J Cancer. 2005 Apr 20;114(4):513-21.

Author: Nihal M, Ahmad N, Mukhtar H, Wood GS.

Affiliation: Department of Dermatology, University of Wisconsin and William S. Middleton Veterans Memorial Hospital, Madison, WI 53706, USA.

Abstract: This study examined the antiproliferative effects of epigallocatechin-3-gallate (EGCG), the major polyphenolic antioxidant present in green tea, in two human melanoma cell lines (A-375 amelanotic malignant melanoma and Hs-294T metastatic melanoma) and normal human epidermal melanocytes (NHEM). EGCG treatment was found to result in a dose-dependent decrease in the viability and growth of both melanoma cell lines. Interestingly, at similar EGCG concentrations, the normal melanocytes were not affected. The data suggest that EGCG causes significant induction of cell cycle arrest and apoptosis of melanoma cells that is mediated via modulations in the cki-cyclin-cdk network and Bcl2 family proteins. Thus, EGCG, alone or in conjunction with current therapies, could be useful for the management of melanoma.

EGCG and Prostate Cancer

Molecular Pathway for (-)-Epigallocatechin-3-Gallate-Induced Cell Cycle Arrest and Apoptosis of Human Prostate Carcinoma Cells

Source: Arch Biochem Biophys. 2003 Feb 1;410(1):177-85

Author: Gupta S, Hussain T, Mukhtar H.

Affiliation: Department of Urology, Jim & Eillen Dicke Research Laboratory, Case Western Reserve University, The Research Institute of University Hospitals of Cleveland, Cleveland, OH 44106, USA.

Abstract: This study showed that green tea polyphenols exert remarkable preventive effects against prostate cancer in a mouse model and many of these effects are mediated by the ability of polyphenols to induce apoptosis in cancer cells. The study tested a hypothesis that EGCG-mediated cell cycle dysregulation and apoptosis is mediated via modulation of cyclin kinase inhibitor (cki)-cyclin-cyclin-dependent kinase (cdk) machinery. The results suggest that EGCG causes an induction of G1 phase ckis, which inhibits the cyclin-cdk complexes operative in the G0/G1 phase of the cell cycle, thereby causing an arrest, which may be an irreversible process ultimately leading to apoptotic cell death. This is the first systematic study showing the involvement of each component of cdk inhibitor-cyclin-cdk machinery during cell cycle arrest and apoptosis of human prostate carcinoma cells by EGCG.

Green Tea Polyphenols Block Endotoxin-Induced Tumor Necrosis Factor-Production and Lethality in a Murine Model

Source: J Nutr. 1998;128(12):2334-40.

Author: Yang F, de Villiers WJ, McClain CJ, Varilek GW.

Affiliation: Graduate Program in Nutritional Sciences, Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA.

Abstract: This study postulated that green tea polyphenols regulate tumor necrosis factor-alpha (TNFalpha) gene expression by modulating NF-KB activation through their antioxidant properties. Tumor necrosis factor-alpha(TNFalpha) plays a pivotal role in inflammations. The study concludes that the anti-inflammatory mechanism of green tea polyphenols is mediated at least in part through down-regulation of TNFalpha gene expression by blocking NF-KB activation. These findings suggest that green tea polyphenols may be effective therapy for a variety of inflammatory processes.

EGCG and Stomach Cancer

Mechanistic Aspects of Green Tea as a Cancer Preventive: Effect of Components on Human Stomach Cancer Cell Lines

Source: Jpn J Cancer Res. 1999 Jul;90(7):733-9

Author: Okabe S, Ochiai Y, Aida M, Park K, Kim SJ, Nomura T, Suganuma M, Fujiki H.

Affiliation: Saitama Cancer Center Research Institute.

Abstract: The aim of this study was to understand the mechanisms of anticarcinogenesis through the examination of growth inhibition by EGCG in human stomach cancer cell lines established at Seoul National University (SNU cell lines). Inhibition by EGCG of [3H]thymidine incorporation into eight SNU cell lines was observed in relation to transforming growth factor-beta (TGF-beta) responsiveness. This study demonstrates that EGCG and other tea polyphenols may interact with various transcription factors, in addition to AP-1 and NF-kappa B, in nuclei of various cells, resulting in inhibition of TNF-alpha gene expression and TNF-alpha release.

Mechanisms of Cancer Prevention by Tea Polyphenols Based on Inhibition of TNF-Alpha Expression

Source: Biofactors. 2000;13(1-4):67-72

Author: Suganuma M, Sueoka E, Sueoka N, Okabe S, Fujiki H.

Affiliation: Saitama Cancer Center Research Institute, Japan.

Abstract: This animal study with TNF-alpha-deficient mice has revealed that TNF-alpha is an essential factor in tumor promotion. The study found that EGCG dose-dependently inhibited AP-1 and NF-kappaB activation in BALB/3T3 cells treated with okadaic acid, resulting in inhibition of TNF-alpha gene expression. Furthermore, treatment with 0.1% green tea extract in drinking water reduced TNF-alpha gene expression as well as TNF-alpha protein level in the lung of TNF-alpha transgenic mice; and IL-1beta and IL-10 gene expression in the lung was also inhibited by treatment with green tea extract, indicating that green tea inhibits both TNF-alpha and the cytokines induced by TNF-alpha in organs. The study reports the synergistic effects of EGCG and cancer preventive agents such as tamoxifen and sulindac, on cancer preventive activity. All these results show that green tea is efficacious as a non-toxic cancer preventive for humans.

Gastric Cancer and

Gastric Cancer and Vit D3 + Cisplatin combo.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24573222

Author: Bao A, et al.

Affiliation: Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.

Abstract: 1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] plays an anticancer role in multiple types of cancer and potentiates the cytotoxic effects of several common chemotherapeutic agents. The hypercalcemia caused by 1,25(OH)2D3 alone or resistance to cisplatin weaken the anticancer effects of vitamin D. Thus, in this study, researchers aimed to investigate the synergistic effects of 1,25(OH)2D3 and cisplatin on the apoptosis and cell cycle progression of gastric cancer cells. BGC-823 human gastric cancer cells were treated with 1,25(OH)2D3 or cisplatin alone, or a combination of both agents. Cell apoptosis was assessed by TUNEL assay and flow cytometry. The expression of the apoptosis-related proteins, poly(ADP-ribose) polymerase (PARP), Bax, Bcl-2, caspase-3 and caspase-8, was examined using immunoblot analysis. ERK and AKT phosphorylation were examined by immunoblot analysis. The cell cycle distribution was determined by propidium iodide staining and flow cytometric analysis. p21 and p27 protein expression was also examined using immunoblot analysis. Our results revealed that co-treatment with 1,25(OH)2D3 enhanced cisplatin-induced apoptosis and upregulated the expression of Bax, and promoted the cleavage of PARP and caspase-3. The phosphorylation levels of ERK and AKT were reduced following combined treatment with 1,25(OH)2D3 and cisplatin. The percentage of cells in the G0/G1 phase was greater in the cells treated with the combined treatment than in those treated with either 1,25(OH)2D3 or cisplatin alone. p21 and p27 expression was upregulated following co-treatment with both agents. The results of this study suggest that 1,25(OH)2D3 potentiates cisplatin-mediated cell growth inhibition and cell apoptosis, which involves the upregulation of Bax, a decrease in ERK and AKT phosphorylation levels, and increased p21 and p27 levels.

Association between dietary antioxidant vitamins intake/blood level and risk of gastric cancer.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24510802

Author: Li P, et al.

Affiliation: Department of Epidemiology and Health Statistics, Zhejiang University School of Public Health, Hangzhou, China.

Abstract: The researchers aimed to systematically evaluate the association between dietary intake/blood levels of antioxidant vitamins (vitamin C, vitamin E, â-carotene, and á-carotene) and gastric cancer risk. Systematic literature searches were conducted until April 2013 in Pubmed and Embase to identify relevant studies. Either a fixed- or a random-effects model was adopted to estimate overall odds ratios (ORs). Dose-response, meta-regression, subgroup, and publication bias analyses were applied. Forty articles were finally included in the present study. Higher dietary intake of vitamin C, vitamin E, â-carotene, and á-carotene was inversely associated with gastric cancer risk. Subgroup analyses suggested the effects of these antioxidant vitamins were different in gastric cancer subtypes. As indicated by dose-response analysis, a 100 mg/day increment of vitamin C intake conferred an OR of 0.78 (95% CI 0.67-0.90); a 15 mg/day increment of vitamin E intake conferred an OR of 0.79 (95% CI 0.66-0.94); and a 5 mg/day increment in â-carotene intake conferred an OR of 0.80 (95% CI 0.60-1.04). No significant association was observed between blood vitamin C, á-tocopherol, ã- tocopherol, â-carotene and á-carotene levels and gastric cancer risk. In conclusion, dietary intake of vitamin C, vitamin E, â-carotene and á-carotene was inversely associated with gastric cancer risk while no such association was observed for blood levels of these antioxidant vitamins, thus the results should be interpreted cautiously.

Leukemia

In vivo and in vitro antitumor effects of nutrient mixture in murine leukemia cell line P-388.

Source: Experimental Oncology 2011;33(2):71-7.

Author: Roomi MW, Roomi NW, Bhanap B, Rath M, Niedzwiecki A.

Affiliation: Dr. Rath's Research Institute, Cancer Division, Santa Clara, California 95050, USA.

Abstract: Leukemia is characterized by uncontrolled marrow cell proliferation and metastatic foci. The authors investigated the antitumor potential of a nutrient mixture on malignant leukemia P-388 cells. The nutrient mixture containing lysine, proline, ascorbic acid, green tea extract and other nutrients is formulated to target key pathways in cancer progression. The cells were treated with the mixture, and tested at doses 0, 10, 50, 100, 500 and 1000 μg/ml in triplicates. The effects were evaluated by cell proliferation, Matrigel invasion, cell morphology and apoptosis. The in vivo effect was measured in male nude mice (n = 12) inoculated with P-388 cells. After randomly dividing in two groups, each group was fed regular and the nutrient mixture supplemented diet and the mice were sacrificed after four weeks. Results: The nutrient mixture decreased P-388 cell proliferation at 500 and 1000 μg/ml. Only 10% cells were viable at 1000 μg/ml. Matrigel invasion was significantly inhibited in a dose dependent manner with virtually total inhibition at 1000 μg/ml. Cell morphological features notably changed with dose increase to 1000 μg/ml. Analysis of apoptotic cells on live green caspase kit exhibited gradual increase with the increasing dose of the nutrient mixture, and at 1000 μg/ ml 92% of P-388 cells were in late apoptosis. Tumors in the group of mice supplemented with the nutrient mixture had 50% lower weight compared to the tumors in control group (p = 0.0105). Histopathologically, both the groups of tumors were similar, yet size of tumors in the group treated with the nutrient mixture was considerably smaller. Conclusion: These results indicate that the nutrient mixture exhibited significant action against multiple targets in P-388 leukemia and may have potential in human leukemia.

Phase II trial of daily, oral green tea extract in patients with asymptomatic, Rai stage 0-II chronic lymphocytic leukemia (CLL).

Source: Journal of Clinical Oncology 28:15s, 2010 (suppl; abstr 6522)

Author: Shanafelt TD, Call T, Zent CS, LaPlant B, Leis JF, Bowen D et al

Affiliation: Mayo Clinic Rochester, Rochester, MN; Mayo Clinic Arizona, Scottsdale, AZ

Abstract: Green tea has long been touted as a health promoting substance. In vitro testing and a phase I trial suggest the green tea extract epigallocatechin 3 gallate(EGCG) may have clinical efficacy for chronic lymphocytic leukemia (CLL) patients. To follow-up on these results, the authors performed a phase II trial of daily EGCG in patients with CLL. 42 eligible patients received EGCG 2000 mg twice daily for up to 6 months. Patients received a median of 6 cycles of treatment (range: 1-6). Accrual to the trial is complete. Thirty-one patients have completed study therapy while 11 patients have not yet completed treatment. The most common side effects included transaminitis, abdominal pain and nausea. Only 2/48 (4.8%) patients experienced grade 3 toxicity. One patient experienced an NCI WG* partial remission. Other signs of clinical activity were observed with 13 (31%) patients experiencing a sustained ≥ 20% reduction in ALC and 19 of 29 (66%) patients with palpable adenopathy experiencing at least a 50% reduction in the sum of the products of all nodal areas during treatment. Overall 28 (67%) patients fulfilled the criteria for a biologic response (JCO 27:3808) based on attaining either a sustained ≥ 20% decline in ALC and/or a ≥ 50% reduction in the sum of the products of all nodal areas at some point during the 6 months of active treatment. Conclusions: Daily oral EGCG in the Polyphenon E preparation was well tolerated by CLL patients in this phase II trial. Declines in ALC and/or lymphadenopathy were observed in the majority of patients. EGCG containing green tea extracts may have potential as disease stabilizing agents in patients with early-stage CLL.

*National Cancer Institute (NCI) Working Group (WG) Criteria

Phase I Trial of Daily Oral Polyphenon E in Patients With Asymptomatic Rai Stage 0 to II Chronic Lymphocytic Leukemia

Source: Journal of Clinical Oncology 2009; 27(23): 3808–3814.

Author: Shanafelt Tait D., Call Tim G., Zent Clive S., LaPlant Betsy, Bowen Deborah A., Roos Michelle, Secreto Charla R., Ghosh Asish K., Kabat Brian F., Lee Mao-Jung, Yang Chung S., Jelinek Diane F., Erlichman Charles, and Kay Neil E.

Affiliation: Department of Internal Medicine, Division of Hematology; Division of Biostatistics, and Departments of Immunology and Oncology, Mayo Clinical, Rochester, MN; and the Department of Chemical Biology, and the Ernest Mario School of Pharmacy Rutgers, the State University of New Jersey, Piscataway, NJ.

Abstract: This study was done to define the optimal dose of Polyphenon E for chronic daily administration and tolerability in patients with chronic lymphocytic leukemia (CLL). Previously untreated patients with asymptomatic Rai stage 0 to II CLL were eligible for participation. Polyphenon E with a standardized dose of epigallocatechin-3-gallate (EGCG) was administered using the standard phase I design with three to six patients per dose level (range, 400 to 2,000 mg by mouth twice a day). Trough plasma EGCG levels were measured 1 month after initiation of therapy. Response was classified using the National Cancer Institute (NCI) Working Group (WG) Criteria. Thirty-three eligible patients were accrued to dose levels 1 to 8. The maximum-tolerated dose was not reached. The most common adverse effects included transaminitis (33%, all grade 1), abdominal pain (30% grade 1, 0% grade 2, and 3% grade 3), and nausea (39% grade 1 and 9% grade 2). One patient experienced an NCI WG partial remission. Other signs of clinical activity were also observed, with 11 patients (33%) having a sustained ≥ 20% reduction in absolute lymphocyte count (ALC) and 11 (92%) of 12 patients with palpable adenopathy experiencing at least a 50% reduction in the sum of the products of all nodal areas during treatment. Trough plasma EGCG levels after 1 month of treatment ranged from 2.9 to 3,974 ng/mL (median, 40.4 ng/mL). Conclusion: Daily oral EGCG in the Polyphenon E preparation was well tolerated by CLL patients in this phase I trial. Declines in ALC and/or lymphadenopathy were observed in the majority of patients. A phase II trial to evaluate efficacy using 2,000 mg twice a day began in November 2007.

Liver Cancer

Liver Cancer, Trans retinoic acid and Vit D3

Source: http://www.ncbi.nlm.nih.gov/pubmed/17166369

Author: Lu HQ, Zheng J.

Affiliation: Institute of Molecular Pathology, Department of Pathology and Pathophysiology, School of Basic Medical Science, Southeast University, Nanjing, Jiangsu, P. R. China.

Abstract: All-trans retinoic acid (ATRA) and 1,25-dihydroxy vitamin D3 [1,25(OH)2D3] can inhibit the proliferation of tumor cells and induce their differentiation. They have been used to treat leukemia, but their effects on solid tumors remain unclear. This study was to investigate the effects of ATRA and 1,25(OH)2D3 on growth and cell cycle of human hepatoma cell line HepG2, and explore the molecular mechanism. After HepG2 cells were treated with ATRA, 1,25(OH)2D3, or the combination of both chemicals, cell survival was assessed by MTT assay, morphologic changes were observed under light microscope, cell cycle and apoptosis were determined by flow cytometry (FCM) with dual staining of AnnexinV/PI, and the expression of p21(WAF/CIP1) and p27(KIP1) mRNA and protein were determined by reverse transcription-polymerase chain reaction (RT-PCR) and FCM. ATRA and 1,25(OH)2D3, used alone or in combination, inhibited the growth of HepG2 cells in a time- and dose-dependent manner. The inhibition was more obvious in the combination group than in ATRA group and 1,25(OH)2D3 group. FCM analysis indicated that 10 nmol/L 1,25(OH)2D3, used alone or in combination with ATRA for 72 h, strongly induced G1 phase arrest of HepG2 cells, but 1 micromol/L ATRA did not show obvious effect. All of them induced apoptosis. The mRNA level of p21(WAF/CIP1) was enhanced by 35% and 56% of control in the cells treated with 10 nmol/L 1,25(OH)2D3 or 1,25(OH)2D3 combined with ATRA for 24 h. The combination of 1,25(OH)2D3 and ATRA markedly enhanced the protein levels of p21(WAF/CIP1) and p27(KIP1) as compared with 1,25(OH)2D3 alone, and 1 micromol/L ATRA did not enhance the protein levels of p21(WAF/CIP1) and p27(KIP1) in HepG2 cells. ATRA and 1,25(OH)2D3 could inhibit growth and induce apoptosis of HepG2 cells, and the molecular basis of the cell cycle blockade by 1,25(OH)2D3 may be associated with the up-regulation of CDK inhibitors p21(WAF/CIP1) and p27(KIP1), which mediate G1 arrest. Furthermore, the combination of ATRA and 1,25(OH)2D3 can exert synergistic inhibitory effect on the growth of HepG2 cells.

Lung Cancer

Chemotherapy Alone vs. Chemotherapy Plus High Dose Multiple Antioxidants in Patients with Advanced Non Small Cell Lung Cancer

Source: J Am Coll Nutr 2005;24(1): 16-21

Author: Ashutosh Kumar Pathak, MBBS, PhD, Manisha Bhutani, MD, DM, et al

Affiliation: Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, INDIA

Abstract: In vitro and animal studies suggest that antitumor effect of chemotherapeutic agents may be enhanced by antioxidants. Therefore, we initiated a clinical study to test the efficacy of high-dose multiple antioxidants (vitamins C, E and beta carotene) as an adjunct to chemotherapy (paclitaxel and carboplatin) in non-small-cell lung cancer. The results do not support the concern that antioxidants might protect cancer cells from the free radical damage induced by chemotherapy. Larger trials are needed to demonstrate whether high-dose multiple antioxidants in conjunction with chemotherapy increase the response rates and/or survival time in advanced lung cancer.

Vitamin E may affect the life expectancy of men, depending on dietary vitamin C intake and smoking

Source: Age and ageing 2011; 40(2): 215-220

Author: Hemilä H and Kaprio J.

Affiliation: Department of Public Health, University of Helsinki, Finland

Abstract: Antioxidants might protect against oxidative stress, which has been suggested as a cause of aging. The Alpha-Tocopherol-Beta-Carotene (ATBC) Study recruited males aged 50–69 years who smoked at least five cigarettes per day at the baseline. The current study was restricted to participants who were followed up past the age of 65. Deaths were identified in the National Death Registry (1,445 deaths). The authors constructed Kaplan–Meier survival curves for all participants, and for four subgroups defined by dietary vitamin C intake and level of smoking. They also constructed Cox regression models allowing a different vitamin E effect for low and high age ranges. Among all 10,837 participants, vitamin E had no effect on those who were 65–70 years old, but reduced mortality by 24% when participants were 71 or older. Among 2,284 men with dietary vitamin C intakes above the median who smoked less than a pack of cigarettes per day, vitamin E extended lifespan by 2 years at the upper limit of the follow-up age span. In this subgroup, the survival curves of vitamin E and no-vitamin E participants diverged at 71 years. In the other three subgroups covering 80% of the participants, vitamin E did not affect mortality. Conclusions: this is the first study to strongly indicate that protection against oxidative stress can increase the life expectancy of some initially healthy population groups. Nevertheless, the lack of effect in 80% of this male cohort shows that vitamin E is no panacea for extending life expectancy.

Dietary alpha-, beta-, gamma- and delta-tocopherols in lung cancer risk

Source: International journal of cancer 2008;123(5):1173-80

Author: Mahabir S, Schendel K, Dong YQ, Barrera SL, Spitz MR, Forman MR.

Affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, USA.

Abstract: Studies of vitamin E and cancer have focused on the alpha-tocopherol form of the vitamin. However, other forms of vitamin E, in particular gamma-tocopherol may have unique mechanistic characteristics relevant to lung cancer prevention. In an ongoing study of 1,088 incident lung cancer cases and 1,414 healthy matched controls, the authors studied the associations between 4 tocopherols (alpha-, beta-, gamma-, and delta-tocopherol) in the diet and lung cancer risk. No significant association between delta-tocopherol intake and lung cancer risk was detected. When the 4 tocopherols were summed as total tocopherol intake, a monotonic risk reduction was also observed. When the other tocopherols were entered in the model, only the association with dietary alpha-tocopherol intake remained significant; i.e., increasing intake of dietary alpha-tocopherol accounted for 34-53% reductions in lung cancer risk.

Serum B vitamin levels and risk of lung cancer.

Source: JAMA. 2010; 303(23):2377-85

Author: Johansson M, Relton C, Ueland PM, Vollset SE, et al.

Affiliation: International Agency for Research on Cancer, Lyon, France.

Abstract:

B vitamins and factors related to 1-carbon metabolism* help to maintain DNA integrity and regulate gene expression and may affect cancer risk. This study was conducted to investigate if 1-carbon metabolism factors are associated with onset of lung cancer. The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 519,978 participants from 10 countries between 1992 and 2000, of who 385,747 donated blood. By 2006, 899 lung cancer cases were identified and 1770 control participants were individually matched by country, sex, date of birth, and date of blood collection. Serum levels were measured for 6 factors of 1-carbon metabolism and cotinine. Measured were odds ratios (ORs) of lung cancer by serum levels of 4 B vitamins (B(2), B(6), folate [B(9)], and B(12)), methionine, and homocysteine. After accounting for smoking, a lower risk for lung cancer was seen for elevated serum levels of B(6), as well as for serum methionine. Similar and consistent decreases in risk were observed in never, former, and current smokers, indicating that results were not due to confounding by smoking. The magnitude of risk was also constant with increasing length of follow-up, indicating that the associations were not explained by preclinical disease. A lower risk was also seen for serum folate, although this was apparent only for former and current smokers. When participants were classified by median levels of serum methionine and B(6), having above-median levels of both was associated with a lower lung cancer risk overall, as well as separately among never, former, and current smokers. Conclusion: Serum levels of vitamin B(6) and methionine were inversely associated with risk of lung cancer.

*The 1-carbon transformations require two cofactors especially: folic acid and vitamin B12. Several compounds that interfere with folic acid metabolism are used in clinical medicine as inhibitors of cancer cells or bacterial growth. The folate pathway is central to any study related to DNA methylation, dTMP synthesis or purine synthesis. Differential methylation (e.g. hypermethylation of tumor suppressors) as well as disturbances in nucleotide synthesis and repair, are associated with several forms of cancer. There are also indications that hypermethylation is involved in the progression of adenomas to cancer. The pathway is also illustrative of the role of a number of B vitamins, including vitamin B12 (cobalamine) which is important for the synthesis of folate (vitamin B9) and of methionine.

Vitamin D intake and lung cancer risk in the Women's Health Initiative.

Source: http://www.ncbi.nlm.nih.gov/pubmed/23966428

Author: Cheng TY, Lacroix AZ, Beresford SA, Goodman GE, et al.

Affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, et al.

Abstract: Prior research suggests that vitamin D protects against lung cancer only among certain subgroups. The authors investigated whether vitamin D intake was associated with lung cancer and explored whether vitamin A intake modified the association. Prospective cohort data from 128,779 postmenopausal women, including 1771 incident lung cancers in the Women's Health Initiative (Clinical Trials and Observational Study) 1993-2010, were analyzed. Twelve percent of women received active intervention (1 g Ca + 400 IU vitamin D3/d) in the Calcium/Vitamin D Trial. Baseline total intake included both dietary intake (from food-frequency questionnaires) and supplement intake (from bottle labels). HRs were estimated by Cox proportional hazard models. No significant association was observed overall. Among never smokers, a total vitamin D intake ¡Ý400 IU/d was significantly associated with lower risks of lung cancer. No significant effect modification of total vitamin A intake on the association between total vitamin D intake and lung cancer was found. However, the Calcium/Vitamin D Trial active intervention was significantly associated with a lower lung cancer risk only among women with a vitamin A intake <1000 ¦Ìg/d retinol activity equivalents. Conclusion: Vitamin D intake was associated with a lower lung cancer risk in never-smoking, postmenopausal women. Lower vitamin A intake may be important for a beneficial association of 1 g Ca + 400 IU vitamin D3 supplementation with lung cancer.

Melanoma (Skin Cancer)

Association of Vitamin A and Carotenoid Intake with Melanoma Risk in a Large Prospective Cohort

Source: The journal of investigative dermatology 2012; 132:1573–1582

Author: Asgari MM, Brasky TM and White E

Affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, California, USA; Department of Dermatology, University of California, San Francisco, San Francisco, California, USA; Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA; Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

Abstract: Laboratory data suggest that intake of vitamin A and carotenoids may have chemopreventive benefits against melanoma, but epidemiological studies examining the association have yielded conflicting results. The authors examined whether dietary and supplemental vitamin A and carotenoid intake was associated with melanoma risk among 69,635 men and women who were participants of the VITamins And Lifestyle (VITAL) cohort study in western Washington. After an average of 5.84 years of follow-up, 566 incident melanomas were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of melanoma associated with dietary, supplemental, and total vitamin A and carotenoid intake after adjusting for melanoma risk factors. Baseline use of individual retinol supplements was associated with a significant reduction in melanoma risk. High-dose (>1,200 μg per day) supplemental retinol was also associated with reduced melanoma risk, as compared with non-users. The reduction in melanoma risk was stronger in sun-exposed anatomic sites. There was no association of melanoma risk with dietary or total intake of vitamin A or carotenoids. Conclusion: Retinol supplementation may have a preventative role in melanoma among women.

Randomized controlled trial of oral omega-3 PUFA in solar-simulated radiation-induced suppression of human cutaneous immune responses.

Source: http://www.ncbi.nlm.nih.gov/pubmed/23364005

Author: Pilkington SM, Massey KA, Bennett SP, Al-Aasswad NM, et al.

Affiliation: Institute of Inflammation and Repair, University of Manchester, Manchester, UK.

Abstract: Skin cancer is a major public health concern, and the majority of cases are caused by solar ultraviolet radiation (UVR) exposure, which suppresses skin immunity. Omega-3 (n-3) PUFAs protect against photoimmunosuppression and skin cancer in mice, but the impact in humans is unknown. The authors hypothesized that EPA-rich n-3 PUFA would abrogate photoimmunosuppression in humans. Therefore, a nutritional study was performed to assess the effect on UVR suppression of cutaneous cell-mediated immunity (CMI) reflected by nickel contact hypersensitivity (CHS). In a double-blind, randomized controlled study, 79 volunteers (nickel-allergic women, 22-60 y old, with phototype I or II) took 5 g n-3 PUFA-containing lipid (70% EPA plus 10% DHA) or a control lipid daily for 3 mo. After supplementation, nickel was applied to 3 skin sites preexposed on 3 consecutive days to 1.9, 3.8, or 7.6 J/cm(2) of solar-simulated radiation (SSR) and to 3 unexposed control sites. Nickel CHS responses were quantified after 72 h and the percentage of immunosuppression by SSR was calculated. Erythrocyte [red blood cell (RBC)] EPA was measured by using gas chromatography. SSR dose-related suppression of the nickel CHS response was observed in both groups. Photoimmunosuppression appeared less in the n-3 PUFA group than in the control group. The difference was greatest at 3.8 J/cm(2) SSR. Postsupplementation RBC EPA was 4-fold higher in the n-3 PUFA group than in the control group, which confirmed the EPA bioavailability. Conclusion: Oral n-3 PUFAs appear to abrogate photoimmunosuppression in human skin, providing additional support for their chemopreventive role.

Vitamin D and melanoma.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24494045

Author: Field S, et al.

Affiliation: Section of Epidemiology and Biostatistics; University of Leeds; Leeds, UK.

Abstract: Recreational sun exposure and sunburn are causal for melanoma but the risk is strongly genetically determined. Health promotion advice about sun protection should be aimed at susceptible individuals (pale skin, freckles, large numbers of melanocytic nevi and a family history). Researchers discuss here the evidence that sun-sensitive people have lower vitamin D levels and that, in practice, it is very difficult for such individuals to achieve sufficient levels without supplementation in the UK at least. The study’s conclusion is that melanoma susceptible sun-avoidant individuals should be advised to avoid insufficiency by supplementation. Vitamin D is anti-proliferative in vitro for some melanoma cell lines. In a large melanoma cohort we have observed that lower serum 25-hydroxyvitamin D2/D3 levels at diagnosis were associated with thicker tumors and poorer prognosis (study as yet not validated). In the UK, melanoma patients commonly have sub-optimal 25-hydroxyvitamin D2/D3 levels at and post diagnosis.

Oesophageal Cancer

Vitamin D3 and Beta-carotene Deficiency is Associated with Risk of Esophageal Squamous Cell Carcinoma - Results of a Case-control Study in China.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24568502

Author: Huang GL, et al.

Affiliation: Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, China

Abstract: The aim of this study was to evaluate roles of vitamin D3 (VD3) and beta-carotene (BC) in the development of esophageal squamous cell carcinoma (ESCC) in a high-risk area, Huai'an District, Huai'an City, China. 100 new ESCC diagnosed cases from 2007 to 2008 and 200 residency- age-, and sex-matched healthy controls were recruited. Data were collected from questionnaires, including a food frequency questionnaire (FFQ) to calculate the BC intake, and reversed phase high-performance liquid chromatography (RP-HPLC) was used to measure the serum concentrations of BC and VD3. Odds ratios (OR) and 95% confidence intervals (CI) were calculated in conditional logistic regression models. The average dietary intake of BC was 3322.9 ìg (2032.4- 5734.3) in the case group and 3626.8 ìg (1961.9-5827.9) in control group per capita per day with no significant difference by Wilcoxon test. However, the levels of VD3 and BC in the case group were significantly lower than in the control group. The OR values of the highest quartile and the lowest quartile of VD3 and BC in serum samples were both 0.13. These results add to the evidence that high circulating levels of VD3 and BC are associated with a reduced risk of ESCC in this Chinese population.

Ovarian cancer and curcumin

Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway.

Source: Clinical cancer research 2001; 13(11): 3423-30

Author: Lin YG, Kunnumakkara AB, Nair A, Merritt WM, Han LY, Armaiz-Pena GN, Kamat AA, Spannuth WA, Gershenson DM, Lutgendorf SK, Aggarwal BB, Sood AK.

Affiliation: Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, USA.

Abstract: Curcumin, a component of turmeric, has been shown to suppress inflammation and angiogenesis largely by inhibiting the transcription factor nuclear factor-kappaB (NF-kappaB)*. This study evaluates the effects of curcumin on ovarian cancer growth using an orthotopic murine model* of ovarian cancer. In vitro and in vivo experiments of curcumin with and without docetaxel* were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8-MDR in athymic mice. Curcumin inhibited inducible NF-kappaB activation and suppressed proliferation in vitro. In vivo dose-finding experiments revealed that 500 mg/kg orally was the optimal dose needed to suppress NF-kappaB and signal transducers and activators of transcription 3 activation and decrease angiogenic cytokine expression. CONCLUSION: Based on significant efficacy in preclinical models, curcumin-based therapies may be attractive in patients with ovarian carcinoma.

• NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection (kappa light chains are critical components of immunoglobulins). Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development.
• Murine model: studies done in rats and mice
• Docetaxel (Taxotere®) is a chemotherapy drug that is usually given to treat breast cancer, prostate cancer and non-small cell lung cancer.

Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth.

Source: Journal of ovarian research 2010; 3:11

Author: Yallapu MM, Maher DM, Sundram V, Bell MC, Jaggi M, Chauhan SC.

Affiliation: Cancer Biology Research Center, Sanford Research/University of South Dakota, USA.

Abstract: Chemo/radio-resistance is a major obstacle in treating advanced ovarian cancer. The efficacy of current treatments may be improved by increasing the sensitivity of cancer cells to chemo/radiation therapies. Curcumin is a naturally occurring compound with anti-cancer activity in multiple cancers; however, its chemo/radio-sensitizing potential is not well studied in ovarian cancer. Herein, the scientists demonstrate the effectiveness of a curcumin pre-treatment strategy for chemo/radio-sensitizing cisplatin* resistant ovarian cancer cells. To improve the efficacy and specificity of curcumin induced chemo/radio sensitization, we developed a curcumin nanoparticle formulation conjugated with a monoclonal antibody specific for cancer cells. Curcumin pre-treatment considerably reduced the dose of cisplatin and radiation required to inhibit the growth of cisplatin resistant ovarian cancer cells. CONCLUSION: Curcumin pre-treatment enhances chemo/radio-sensitization in A2780CP ovarian cancer cells through multiple molecular mechanisms. Therefore, curcumin pre-treatment may effectively improve ovarian cancer therapeutics. A targeted nanoparticle formulation of curcumin is feasible and may improve the in vivo therapeutic efficacy of curcumin.

• Cisplatin is a chemotherapy drug. It is used to treat various types of cancers.

Pancreatic Cancer

Predicted vitamin D status and pancreatic cancer risk in two prospective cohort studies.

Source: Br J Cancer. 2010;102(9):1422-7.

Author: Bao Y, Ng K, Wolpin BM, Michaud DS, Giovannucci E, Fuchs CS.

Affiliation: Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.

Abstract: In this study 118 597 participants in the Nurses' Health Study and Health Professionals Follow-up Study from 1986 to 2006 were followed. During 20 years of follow-up, 575 incident pancreatic cancer cases were identified. Higher 25(OH)D score was associated with a lower risk of pancreatic cancer in these two prospective cohort studies.

Plasma 25-hydroxyvitamin D and risk of pancreatic cancer.

Source: Cancer epidemiology, biomarkers & prevention 2012; 21(1):82-91

Author: Wolpin BM, Ng K, Bao Y, Kraft P, et al

Affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.

Abstract: Laboratory studies suggest that vitamin D may inhibit pancreatic cancer cell growth. However, epidemiologic studies of vitamin D and pancreatic cancer risk have been conflicting. To determine whether prediagnostic levels of plasma 25-hydroxyvitamin D (25[OH]D; IDS Inc.; enzyme immunoassay) were associated with risk of pancreatic cancer, the authors conducted a pooled analysis of nested case-control studies with 451 cases and 1,167 controls from five cohorts through 2008. Median follow-up among controls was 14.1 years in Health Professionals Follow-Up Study (HPFS), 18.3 years in Nurses' Health Study (NHS), 25.3 years in Physicians' Health Study (PHS), 12.2 years in Women's Health Initiative-Observational Study (WHI), and 14.4 years in Women's Health Study (WHS). Logistic regression was used to compare the odds of pancreatic cancer by plasma level of 25(OH)D. Mean plasma 25(OH)D was lower in cases versus controls (61.3 vs. 64.5 nmol/L). In logistic regression models, plasma 25(OH)D was inversely associated with odds of pancreatic cancer. No increased risk was noted in subjects with 25(OH)D =100 nmol/L, as suggested in a prior study. Conclusion: Among participants in five large prospective cohorts, higher plasma levels of 25(OH)D were associated with a lower risk for pancreatic cancer.

Pancreatic cancer risk and levels of trace elements

Source: Gut. 2011 Dec 19. [Epub ahead of print]

Author: Amaral AF, Porta M, Silverman DT, Milne RL, Kogevinas M, Rothman N, Cantor KP, Jackson BP, Pumarega JA, López T, Carrato A, Guarner L, Real FX, Malats N.

Affiliation: Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

Abstract: Background and AimsKnowledge on the aetiology of exocrine pancreatic cancer (EPC) is scant. The best established risk factor for EPC is tobacco smoking. Among other carcinogens, tobacco contains cadmium, a metal previously associated with an increased risk of EPC. This study evaluated the association between concentrations of trace elements in toenails and EPC risk. The study included 118 EPC cases and 399 hospital controls from eastern Spain. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Significantly increased risks of EPC were observed among subjects whose concentrations of cadmium, arsenic and lead were in the highest quartile. High concentrations of selenium and nickel were inversely associated with the risk of EPC. Conclusion: Novel associations are reported of lead, nickel and selenium toenail concentrations with pancreas cancer risk. Furthermore, the results confirm previous associations with cadmium and arsenic. These novel findings, if replicated in independent studies, would point to an important role of trace elements in pancreatic carcinogenesis.

Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

Source: American journal of epidemiology 2010 ;172(1):81-93

Author: Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al

Affiliation: National Cancer Institute, Bethesda, Maryland, USA.

Abstract: Results from epidemiologic studies examining pancreatic cancer risk and vitamin D intake or 25-hydroxyvitamin D (25(OH)D) concentrations (the best indicator of vitamin D derived from diet and sun) have been inconsistent. Therefore, the authors conducted a pooled nested case-control study of participants from 8 cohorts within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) (1974-2006) to evaluate whether prediagnostic circulating 25(OH)D concentrations were associated with the development of pancreatic cancer. In total, 952 incident pancreatic adenocarcinoma cases occurred among participants (median follow-up, 6.5 years). Controls (n = 1,333) were matched to each case by cohort, age, sex, race/ethnicity, date of blood draw, and follow-up time. Conditional logistic regression analysis was used to calculate smoking-, body mass index-, and diabetes-adjusted odds ratios and 95% confidence intervals for pancreatic cancer. Clinically relevant 25(OH)D cutpoints were compared with a referent category of 50-<75 nmol/L. No significant associations were observed for participants with lower 25(OH)D status. However, a high 25(OH)D concentration (> or =100 nmol/L) was associated with a statistically significant 2-fold increase in pancreatic cancer risk overall (odds ratio = 2.12, 95% confidence interval: 1.23, 3.64). Given this result, recommendations to increase vitamin D concentrations in healthy persons for the prevention of cancer should be carefully considered.

Fatty acids found in dairy, protein and unsaturated fatty acids are associated with risk of pancreatic cancer in a case-control study.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24590454

Author: Jansen RJ, et al.

Affiliation: Division of Epidemiology Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

Abstract: Although many studies have investigated meat and total fat in relation to pancreatic cancer risk, few have investigated dairy, fish and specific fatty acids (FAs). The researchers evaluated the association between intake of meat, fish, dairy, specific FAs and related nutrients and pancreatic cancer. In the researchers American-based Mayo Clinic case-control study 384 cases and 983 controls frequency matched on recruitment age, race, sex and residence area (Minnesota, Wisconsin or Iowa, USA) between 2004 and 2009. All subjects provided demographic information and completed 144-item food frequency questionnaire. Logistic regression-calculated odds ratios (ORs) and 95% confidence intervals were adjusted for age, sex, cigarette smoking, body mass index and diabetes mellitus. Significant inverse association between pancreatic cancer and the groupings was as follows: meat replacement, total protein, vitamin B12, zinc, phosphorus, vitamin E, polyunsaturated FAs and linoleic acid. Increased risk associations were observed for saturated FAs, butyric acid, caproic acid, caprylic acid and capric acid. This study suggests that eating a diet high in total protein and certain unsaturated FAs is associated with decreased risk of developing pancreatic cancer in a dose-dependent manner, whereas fats found in dairy increase risk.

Nut consumption and risk of pancreatic cancer in women.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24149179

Author: Bao Y, Hu FB, Giovannucci EL, Wolpin BM, et al.

Affiliation: Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA.

Abstract: Increasing nut intake has been associated with reduced risk of diabetes mellitus, which is a risk factor for pancreatic cancer. The authors prospectively followed 75 680 women in the Nurses' Health Study, and examined the association between nut consumption and pancreatic cancer risk. Participants with a previous history of cancer were excluded. Nut consumption was assessed at baseline and updated every 2 to 4 years. Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards models. The authors documented 466 incident cases of pancreatic cancer. After adjusting for age, height, smoking, physical activity, and total energy intake, women who consumed a 28-g (1 oz) serving size of nuts 2 times per week experienced a significantly lower risk of pancreatic cancer when compared with those who largely abstained from nuts. The results did not appreciably change after further adjustment for body mass index (BMI) and history of diabetes mellitus. The inverse association persisted within strata defined by BMI, physical activity, smoking, and intakes of red meat, fruits, and vegetables. Conclusion: Frequent nut consumption is inversely associated with risk of pancreatic cancer in this large prospective cohort of women, independent of other potential risk factors for pancreatic cancer.

Pancreatic cancer

Prostate Cancer

Dietary zinc and prostate cancer survival in a Swedish cohort.

Source: The American journal of clinical nutrition 2011;93(3):586-93

Author: Epstein MM, Kasperzyk JL, Andrén O, Giovannucci EL, Wolk A, Håkansson N, Andersson SO, Johansson JE, Fall K, Mucci LA.

Affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, USA.

Abstract: Zinc is involved in many essential cellular functions, including DNA repair and immune system maintenance. Although experimental evidence supports a role for zinc in prostate carcinogenesis, epidemiologic data are inconsistent; no data on cancer-specific survival have been reported. The objective of this study was to determine whether dietary zinc assessed near the time of prostate cancer diagnosis is associated with improved disease-specific survival. This population-based cohort consists of 525 men aged <80 y from Örebro County, Sweden, with a diagnosis of prostate cancer made between 1989 and 1994. Study participants completed self-administered food-frequency questionnaires, and zinc intake was derived from nutrient databases. With a median follow-up of 6.4 years, 218 (42%) men died of prostate cancer and 257 (49%) died of other causes. High dietary zinc intake was associated with a reduced risk of prostate cancer-specific mortality in the study population. The association was stronger in men with localized tumors. Zinc intake was not associated with mortality from other causes. These results suggest that high dietary intake of zinc is associated with lower prostate cancer-specific mortality after diagnosis, particularly in men with localized disease.

Phase II Prospective Randomized Trial of a Low-Fat Diet with Fish Oil Supplementation in Men Undergoing Radical Prostatectomy

Source: Cancer prevention research 4(12); 1–10.

Author: Aronson WJ, Kobayashi J, Barnard RJ, et al

Affiliation: Departments of Urology, Molecular and Medical Pharmacology, and Pathology; Center for Human Nutrition, VA Medical Center Greater Los Angeles Healthcare System, Los Angeles, California

Abstract: Preclinical studies suggest lowering dietary fat and decreasing the ratio of omega-6 to omega-3 polyunsaturated fatty acids decreases the risk of prostate cancer development and progression. The authors conducted a phase II randomized trial to test the effect of decreasing dietary fat combined with decreasing the dietary omega-6:omega-3 ratio on biomarkers related to prostate cancer development and progression. Patients undergoing radical prostatectomy were randomly assigned to receive a low-fat diet with 5 grams of fish oil daily (dietary omega-6:omega-3 ratio of 2:1) or a control Western diet (omega-6:omega-3 ratio of 15:1) for four to six weeks prior to surgery. The primary endpoint was change in serum insulin-like growth factor I (IGF-1) between arms. Secondary endpoints were serum IGFBP-1, prostate prostaglandin E2 levels, omega-6:omega-3 fatty acid ratios, COX-2, and markers of proliferation and apoptosis. 55 patients were randomized and 48 completed the trial. There was no treatment difference in the primary outcome. Positive secondary outcomes in the low-fat fish oil versus Western group were reduced benign and malignant prostate tissue omega-6:omega-3 ratios, reduced proliferation (Ki-67 index), and reduced proliferation in an ex vivo bioassay when patient sera was applied to prostate cancer cells in vitro. In summary, 4 to 6 weeks of a low-fat diet and fish oil capsules to achieve an omega-6:omega-3 fatty acid ratio of 2:1 had no effect on serum IGF-1 levels, though in secondary analyses, the intervention resulted in decreased prostate cancer proliferation and decreased prostate tissue omega-6:omega-3 ratios. These results support further studies evaluating reduction of dietary fat with fish oil supplementation on modulating prostate cancer biology.

Effect of a Low-fat Fish Oil Diet on Pro-inflammatory Eicosanoids and Cell Cycle Progression Score in Men Undergoing Radical Prostatectomy.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24169960

Author: Galet C, Gollapudi K, Stepanian S, Byrd JB, et al.

Affiliation: 1Urology, UCLA Department of Urology.

Abstract: The authors previously reported that a 4-6 week low-fat fish oil (LFFO) diet did not affect serum IGF-1 levels (primary outcome) but resulted in lower omega-6 to omega-3 fatty acid ratios in prostate tissue and lower prostate cancer proliferation (Ki67) as compared to a Western diet (WD). In this post-hoc analysis, the effect of the LFFO intervention on serum pro-inflammatory eicosanoids, LTB4 and 15(S)-HETE, and the cell cycle progression (CCP) score were investigated. Serum fatty acids and eicosanoids were measured by gas chromatography and ELISA. CCP score was determined by RT-PCR. Associations between serum eicosanoids, Ki67, and CCP score were evaluated using partial correlation analyses. BLT1 (LTB4 receptor) expression was determined in prostate cancer cell lines and prostatectomy specimens. Serum omega-6 fatty acids and 15(S)-HETE levels were significantly reduced, and serum omega-3 levels were increased in the LFFO group relative to the WD group, whereas there was no change in LTB4 levels. The CCP score was significantly lower in the LFFO compared to the WD group. The 15(S)-HETE change correlated with tissue Ki67 but not with CCP score. The LTB4 change correlated with the CCP score but not with Ki67. The LTB4 receptor BLT1 was detected in prostate cancer cell lines and human prostate cancer specimens. In conclusion, a LFFO diet resulted in decreased 15(S)-HETE levels and lower CCP score relative to a WD.

Specific micronutrient combination inhibits metastasis of melanoma cancer to the lungs

Inhibition of Pulmonary Metatasis of Melanoma B16FO Cells in C57BL/6 Mice by a Nutrient Mixture Consisting of Ascorbic Acid, Lysine, Proline, Arginine, and Green Tea Extract

Source: Experimental Lung Research, 2006 Nov-Dec; 32(10):517-530.

Author: M.W. Roomi, N. Roomi, V. Ivanov, T. Kalinovsky, A. Niedzwiecki, and M. Rath

Affiliation: Dr Rath Research Institute, Santa Clara, CA, USA

Abstract: The primary objective of this animal study was to investigate whether these natural components applied as a synergistic mixture (NM) could inhibit experimentally induced lung metastases in C57BL/6 female mice injected with melanoma B16FO cells. In mice supplemented with NM through the diet the number of metastatic colonies in the lungs was reduced by 63%. In mice who received NM through ip and iv injection the number of lung metastases was reduced by 86%. In mice injected with melanoma cells pretreated with NM no lung metastases were detected, the metastasis was inhibited by 100%. The results of this study show that this nutrient mixture administered in a diet was effective in a significant inhibition of metastasis of B16FO melanoma cells to the lungs. By exposure to higher concentrations of NM, such as obtained through iv or ip delivery, an enhanced inhibitory effect was obtained (up to 86%). It is important to note that the exposure of tumor cells to NM before their injection to the mice completely prevented development of lung tumors (100% inhibition of metastasis). These findings together with earlier results provided by Dr. Rath’s research team clearly indicate that natural nutrient combination (NM) has a high potential in preventing cancer metastasis.

Anti-proliferative and anti-cancer effects of specific micronutrient combination

A Specific Combination of Ascorbic Acid, Lysine, Proline and Epigallocatechin Gallate Inhibits Proliferation and Extracellular Matrix Invasion of Various Human Cancer Cell Lines (2003)

Source: Research Communications in Pharmacology and Toxicology: Emerging Drugs, 2:37-5, 2003.

Author: Netke SP, Roomi MW, Roomi NW, Ivanov V, Niedzwiecki A, Rath M.

Affiliation: Dr Rath Research Institute, Santa Clara, CA, USA

Abstract: This study demonstrates significant anti-proliferative and anti-metastatic effects in vitro against some human cancer cell lines (breast, colon, and melanoma) using a specific combination of ascorbic acid, proline, and lysine. The addition of epigallocatechin gallate (EGCG) to the nutrient mixture enhanced the inhibitory effect on both cellular proliferation and invasion. The proliferation of breast cancer cells (MDA-MB-231) in the presence of AA, P, L and 20 µg/ml of EGCG was reduced to 74%. The proliferation of colon cancer cells (HCT 116) was reduced to 69%, compared to the non-supplemented medium. The increase in concentration of EGCG to 50 µg/ml did not cause much further reduction in the cell number of breast cancer cells, but it did reduce the proliferation of colon cancer cells to 4.6% and melanoma cells to 30% of the control. These results are significant in showing the great potential of the control of cancer growth and metastasis using a safe natural nutrient approach.

Inhibitory effects of synergy of micronutrients in ovarian cancer

Inhibition of Matrix Metalloprotenase-2 Secretion and Invasion by Human Ovarian Cancer Line SK-OV-3 with Lysine, Proline, Arginine, Ascorbic Acid and Green Tea Extract

Source: Journal of Obstetrics and Gynaecology Research, 2006, 32(2):148-154.

Author: M. Waheed Roomi, Vadim Ivanov, Tatiana Kalinovsky, Aleksandra Niedzwiecki, Matthias Rath

Affiliation: Dr Rath Research Institute, Santa Clara, CA, USA

Abstract: This study investigated the effect of Dr. Rath’s nutrient mixture (NM) containing lysine, proline, arginine, ascorbic acid, and epigallocatechin gallate on human ovarian cancer cells SK-OV-3 by measuring: cell proliferation, modulation of MMP-2 and –9 secretion, and cancer cell invasive potential. The tested NM inhibited MMP-2 secretion in a dose-dependent fashion with virtual total inhibition at 50 µg/ml NM concentration. Invasion of human ovarian cancer cells through Matrigel decreased in a dose-dependent fashion, with 90% inhibition at 500 µg/ml NM and 100% inhibition at 1000 µg/ml NM (p<0.0001). The combination of lysine, proline, arginine, ascorbic acid, and green tea extract inhibited critical steps in cancer development and spread, such as MMP secretion and invasion, indicating its potential as a treatment modality against ovarian cancer.

Specific micronutrient combination inhibits tumor growth and demonstrates therapeutic potential in lung cancer

In Vivo and In Vitro Anti-tumor Effect of a Unique Nutrient Mixture on Lung Cancer Cell Line A-549

Source: Experimental Lung Research, 2006, 32:1-13.

Author: M.Waheed Roomi, Vadim Ivanov, Tatiana Kalinovsky, Aleksandra Niedzwiecki, and Matthias Rath

Affiliation: Dr Rath Research Institute, Santa Clara, CA, USA

Abstract: The study investigated the effect of specific nutrient mixture (NM) containing lysine, proline, arginine, ascorbic acid, and green tea extract on the tumor growth of human lung carcinoma cell A-549 xenografts in athymic nude mice. Additionally, the study tested the in vitro antitumor effect of NM on lung carcinoma A-549 cells by measuring: cell proliferation by MTT assay, MMP-2 and –9 secretion by gelatinase zymography and cell invasion through Matrigel. Dr. Rath’s nutrient mixture (NM) strongly suppressed the growth of tumors without adverse effects in nude mice; tumor weight was reduced by 44% (p=0.0001) and tumor burden was reduced by 47% (p<0.0001) with supplementation. The NM also inhibited the secretion of both MMPs in a dose-dependent fashion with virtual total inhibition at 500 µg/ml concentration. The invasion of human lung carcinoma cells through Matrigel was significantly reduced at 100 µg/ml (64%) and totally inhibited at 500-µg/ml concentration of NM (p=0.01). These results suggest NM as a potential non-toxic therapeutic agent for lung cancer.

Vitamin C and Bladder Cancer

Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women

Source: Am J Epidemiol. 2002 Dec 1;156(11):1002-10

Author: Jacobs EJ, Henion AK, Briggs PJ, Connell CJ, McCullough ML, Jonas CR, Rodriguez C, Calle EE, Thun MJ.

Affiliation: Department of Epidemiology and Surveillance Research, American Cancer Society, National Home Office, Atlanta, GA 30329-4251, USA. eric.jacobs@cancer.org

Abstract: The authors of this study examined the association between use of individual vitamin C and vitamin E supplements and bladder cancer mortality among 991,522 US adults in the Cancer Prevention Study II (CPS-II) cohort. Regular vitamin C supplement use (15 or more times per month) was not associated with bladder cancer mortality, regardless of duration (rate ratio (RR) = 0.91, 95% confidence interval (CI): 0.68, 1.20 for <10 years' use; RR = 1.25, 95% CI: 0.91, 1.72 for >or=10 years' use). Regular vitamin E supplement use for 10 years or longer was associated with a reduced risk of bladder cancer mortality (RR = 0.60, 95% CI: 0.37, 0.96), but regular use of shorter duration was not (RR = 1.04, 95% CI: 0.77, 1.40). Results support the hypothesis that long-duration vitamin E supplement use may reduce the risk of bladder cancer mortality.

Are Retinol, Vitamin C, Vitamin E, Folate and Carotenoids Intake Associated with Bladder Cancer Risk? Results from the Netherlands Cohort Study

Source: British Journal of Cancer (2001) 85, 977–983.

Author: M P A Zeegers, R A Goldbohm and P A van den Brandt

Affiliation: Department of Epidemiology, Maastricht University, Maastricht; Department of Nutritional Epidemiology, TNO Nutrition and Food Research, Zeist, The Netherlands

Abstract: The cohort study of 120 852 subjects aged 55–69 years at baseline (1986) conducted in the Netherlands examined the association between vitamins and carotenoids intake, vitamin supplement use, and bladder cancer incidence. Exposure status was measured with a food-frequency questionnaire. The study concludes that dietary or supplemental intake of vitamin A, vitamin C, vitamin E, and intake of folate, and most carotenoids are not associated with bladder cancer. In this study, only β-cryptoxanthin intake appeared to be inversely associated.

Megadose vitamins in bladder cancer: a double-blind clinical trial.

Source: Department of Urology, West Virginia University School of Medicine, Morgantown.

Author: Lamm DL, Riggs DR, Shriver JS, vanGilder PF, Rach JF, DeHaven JI

Affiliation:

Abstract: Epidemiological and laboratory studies suggest that vitamin supplements may be helpful in the prevention of some cancers but clinical trials to date have failed to demonstrate protection with naturally occurring vitamins. Without substantiation of the highly touted benefits of vitamins, few physicians who care for cancer patients have recommended their use. A total of 65 patients with biopsy confirmed transitional cell carcinoma of the bladder enrolled in a randomized comparison of intravesical bacillus Calmette-Guerin (BCG) with or without percutaneous administration was also randomized by closed envelope to therapy with multiple vitamins in the recommended daily allowance (RDA) versus RDA multivitamins plus 40,000 units vitamin A, 100 mg. vitamin B6, 2,000 mg. vitamin C, 400 units vitamin E and 90 mg. zinc. The addition of percutaneous BCG did not significantly lessen tumor recurrence but recurrence after 10 months was markedly reduced in patients receiving megadose vitamins. The 5-year estimates of tumor recurrence are 91% in the RDA arm and 41% in the megadose arm (p = 0.0014, Mantel-Cox). Overall recurrence was 24 of 30 patients (80%) in the RDA arm and 14 of 35 (40%) in the high dose arm (p = 0.0011, 2-tailed Fisher's exact test). Megadose vitamins A, B6, C and E plus zinc decrease bladder tumor recurrence in patients receiving BCG immunotherapy. Further research will be required to identify which ingredient(s) provide this protection.

Vitamin C and Breast Cancer

Ascorbate (Vitamin C) Induces Cell Death Through the Apoptosis-Inducing Factor in Human Breast Cancer Cells

Source: Oncol Rep. 2007 Oct;18(4):811-5

Author: Hong SW, Jin DH, Hahm ES, Yim SH, Lim JS, Kim KI, Yang Y, Lee SS, Kang JS, Lee WJ, Lee WK, Lee MS.

Affiliation: Research Center for Women's Diseases, Division of Biological Sciences, Sookmyung Women's University, Seoul 140-742, Korea.

Abstract: This study demonstrates that ascorbate induces cell death through the apoptosis-inducing factor (AIF) in the human breast cancer cell lines, SK-BR3 and Hs578T, but not in a normal breast cell line, Hs578. Ascorbate treatment caused the nuclear translocation of AIF, which is retained in the mitochondria in healthy cells, but caspase cleavage is not induced. Moreover, MG132, an inhibitor of AIF release from mitochondria, blocked the induction of cell death. Furthermore, cells that had been treated with human AIF-specific siRNA resisted cell death induced by ascorbate, implying that the translocation of AIF from mitochondria to the nucleus is responsible for ascorbate-mediated cell death.

Association Between Breast Cancer and Vitamin C, Vitamin E and Selenium Levels: Results of a Case-Control Study in India.

Source: Asian Pac J Cancer Prev. 2005 Apr-Jun;6(2):177-80

Author: Singh P, Kapil U, Shukla NK, Deo S, Dwivedi SN.

Affiliation: Department of Biostatistics, All India Institute of Medical Sciences, New Delhi 110029, India.

Abstract: This hospital based case-control study conducted in India examined the associations of vitamin C, vitamin E and selenium with breast cancer. One hundred and sixty breast cancer patients and an equal number of normal healthy individuals constituted the study population. Venous blood was collected from the cases and controls for estimation of vitamin C, vitamin E and selenium utilizing standard procedures. The results of the present study thus indicated a strong association of vitamin C, vitamin E and selenium with breast cancer in the Indian population.

Meta-Analysis of Studies on Breast Cancer Risk and Diet, the Role of Fruit and Vegetable Consumption and the Intake of Associated Micronutrients.

Source: European Journal of Cancer, Volume 36, Issue 5, p. 636–646, (March 2000)

Author: S. Gandini,1 H. Merzenich,1,2 C. Robertson,1 P. Boyle1

Affiliation: Division of Epidemiology and Biostatics, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy,1 Bremer Institut für Praeventionsforschung und Sozialmedizin (BIPS), Gruenenstrasse 120, 28199 Bremen, Germany2

Abstract: A meta-analysis was carried out, in order to summarise published data on the relationship between breast cancer, fruit and vegetable consumption and/or the intake of beta-carotene and vitamin C. Relative risks were extracted from 26 published studies from 1982 to 1997. Random and fixed effects models were used. Between studies, heterogeneity was found for vegetables, fruit, vitamin C but not for beta-carotene. This analysis confirms the association between intake of vegetables and, to a lesser extent, fruits and breast cancer risk from published sources.

Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany.

Source: http://www.ncbi.nlm.nih.gov/pubmed/22021693

Author: Vollbracht C, et al.

Affiliation: Pascoe Pharmazeutische Präparate GmbH, Giessen, Germany.

Abstract: The aim of the study was to evaluate under praxis conditions the safety and efficacy of intravenous (i.v.) vitamin C administration in the first postoperative year of women with breast cancer. Epidemiological multicentre cohort study, including 15 gynaecologists and general practitioners representatively distributed in Germany. Data from 125 breast cancer patients in UICC stages IIa to IIIb were selected for the study. A total of 53 of these patients were treated with i.v. vitamin C (supplied as Pascorbin® 7.5 g) additional to standard tumour therapy for at least 4 weeks (study group) and 72 without this additional therapy (control group). Main outcome measures were efficacy in regard to outcome and severity of disease- or therapy-induced complaints during adjuvant chemo- and radiotherapy and aftercare. Comparison of control and study groups revealed that i.v. vitamin C administration resulted in a significant reduction of complaints induced by the disease and chemo-/radiotherapy, in particular of nausea, loss of appetite, fatigue, depression, sleep disorders, dizziness and haemorrhagic diathesis. After adjustment for age and baseline conditions (intensity score before adjuvant therapy, chemotherapy, radiotherapy), the overall intensity score of symptoms during adjuvant therapy and aftercare was nearly twice as high in the control group compared to the study group. No side-effects of the i.v. vitamin C administration were documented. Oxidative stress and vitamin C deficiency play an important role in the etiology of adverse effects of guideline-based adjuvant chemo-/radiotherapy. Restoring antioxidative capacity by complementary i.v. vitamin C administration helps to prevent or reduce disease-, or therapy-induced complaints in breast cancer patients. Complementary treatment of breast cancer patients with i.v. vitamin C was shown to be a well-tolerated optimization of standard tumour-destructive therapies, reducing quality of life-related side-effects.

Vitamin C and Cancer

Ascorbic Acid in the Prevention and Treatment of Cancer

Source: Alternative Medicine Review, Volume 3, Number 3, 1998

Author: Kathleen A. Head, ND

Affiliation: Technical Advisor, Thorne Research, Inc.; Associate Editor, Alternative Medicine Review

Abstract: Vitamin C in high dosages appears to be safe for the majority of individuals. Extensive epidemiological evidence points to the capacity of ascorbic acid to prevent cancer at a number of sites. In addition, some of the limited studies which have been conducted on the use of high dose ascorbate in the treatment of cancer have yielded promising results. The study concludes that “while vitamin C alone may not be enough of an intervention in the treatment of most active cancers, since it appears to improve quality of life and extend survival time, it should be considered as part of a treatment protocol for all patients with cancer, whether they have chosen a primarily orthodox, alternative medical, or complementary approach.”

Pharmacologic Ascorbic Acid Concentrations Selectively Kill Cancer Cells: Action as a Pro-Drug to Deliver Hydrogen Peroxide to Tissues

Source: Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-9. Epub 2005 Sep 12

Author: Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E, Levine M.

Affiliation: Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Abstract: This study goals were to test whether ascorbate killed cancer cells selectively, and if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer and 4 normal cell types was measured by using 1-h exposures. The data indicates that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H(2)O(2), and that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H(2)O(2) may be beneficial.

Vitamin C and Treatment of Cancer: Part I. Abstracts and Commentary from the Scientific Literature.

Source: Townsend Letter for Doctors & Patients - May 1997

Author: Gary Null, PhD; Howard Robins, DPM; Mark Tanenbaum, DPM; & Patrick Jennings

Affiliation:

Abstract: This is a review of the scientific literature as it pertains to the impact of vitamin C on cancer. The questions, "What works?" and "How might it be applied?" were the motivational ones behind this review. Each review includes well-designed studies from peer-reviewed journals. Original journal citations are given, along with capsule descriptions of the original scientific abstracts. This review article notes that approximately 90 studies have been done on the role of vitamin C in cancer prevention, with most finding statistically significant effects. Protective effects have been shown for cancers of the pancreas, oral cavity, stomach, esophagus, cervix, rectum, breast, and lung.

Orthomolecular Oncology Review: Ascorbic Acid and Cancer 25 Years Later.

Source: Integrative Cancer Therapies 2005; 4(1); pp.32-44

Author: Michael J. González, Jorge R. Miranda-Massari, Edna M. Mora, Angelik Guzmán, Neil H. Riordan, Hugh D. Riordan, Joseph J. Casciari, James A. Jackson, and Angel Romá-Franco

Affiliation: University of Puerto Rico, Medical Sciences Campus, Graduate School of Public Health, Department Human Development, Nutrition Program, PO Box 365067, San Juan, PR. mgonzalez@rcm.upr.edu

Abstract: This is a follow-up review of the 1979 article by Cameron, Pauling, and Leibovitz published in Cancer Reasearch. The objective of this review is to provide an updated scientific basis for the use of ascorbic acid, especially intravenously as adjuvant treatment in pharmacological nutritional oncology. In this updated version, the authors address general aspects of ascorbic acid and cancer that have been presented before, while reviewing, analyzing, and updateing new existing literature on the subject. In addition, they present and discuss their own mechanistic hypothesis on the effect of ascorbic acid on the cancer cell.

Intravenous Ascorbic Acid: Protocol for Its Application and Use

Source: Puerto Rico Health Sciences Journal (2003) 22:3, 287-290

Author: Hugh D. Riordan, Ronald E. Hunninghake, Neil H. Riordan, James A. Jackson, Xiao LongMeng, Paul Taylor, et al.

Affiliation: Center for the Improvement of Human Functioning, Biocommunications Research Institute, Wichita, KS, USA.

Abstract: This publication describes a clinical protocol that has been developed over the past twenty years utilizing high dose IV AA as therapy for cancer. This includes principles of treatment, rationale, baseline workup, infusion protocol, precautions and side effects. Ascorbate administered in pharmacological doses enhances various parameters associated with better prognosis. There is also evidence that physiologically attainable concentrations by intravenous administration are selectively toxic to cancer; contrary to the limited levels of ascorbate that can be reached by oral intakes. Moreover, there is evidence of synergism between the conventional methods for cancer treatment (surgery, radiation and chemotherapy) when utilized with ascorbate.

Rethinking Vitamin C and Cancer: An Update on Nutritional Oncology

Source: Cancer Prevention International (1998) 3: 215-234

Author: M.J. Gonzalez, E. Mora, N.H. Riordan, H.D. Riordan and P. Mojica

Affiliation: University of Puerto Rico, Medical Sciences Campus, Graduate School of Public Health, Department Human Development, Nutrition Program, PO Box 365067, San Juan, PR. mgonzalez@rcm.upr.edu

Abstract: This article is an attempt to ease the existing controversy while providing an updated scientific basis for the use of vitamin C in nutritional oncology. This article addresses general aspects of vitamin C and cancer, while reviewing and analyzing existing literature on the subject. In addition, presents and discusses hypothesis on the effect of vitamin C on cancer (solid tumors).

Intravenous Ascorbate as a Tumor Cytotoxic Chemotherapeutic Agent

Source: Medical Hypotheses (1995), 44, 207-213

Author: N. H. Riordan, H. D. Riordan, X. Meng, Y. Li and J. A. Jackson

Affiliation: Project RECNAC, Bio-Communications Research Institute, Wichita, Kansas 67219, USA

Abstract: This study shows that sufficient evidence exists to support the testing of intravenous AA for extended periods as a cytotoxic chemotherapy agent, in doses high enough to maintain plasma levels above those which have been found to be preferentially cytotoxic to tumor cells in vitro. In the presented study altogether, six patients have been infused intravenously with similar doses of AA over 8-h periods with no reported side-effects. In all cases, the patients had either been given no further therapeutic options by their oncologists, had refused further conventional treatment, or in one case, requested the use of AA in conjunction with standard chemotherapy. AA is relatively non-toxic and is preferentially cytotoxic to tumor cells at levels attainable in human plasma, at least in vitro. The study concludes that further research on the in vivo effects and mechanism of AA’s preferential cytotoxicity need to be performed.

Intravenously Administered Vitamin C as Cancer Therapy: Three Cases

Source: Canadian Medical Association Journal 2006;174(7):937-42

Author: Sebastian J. Padayatty, Hugh D. Riordan, Stephen M. Hewitt, Arie Katz, L. John Hoffer and Mark Levine

Affiliation: Molecular and Clinical Nutrition Section, Bldg. 10, Rm 4D52–MSC 1372, National Institutes of Health, Bethesda MD 20892–1372; MarkL@mail.nih.gov

Abstract: This study found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. Accumulated data confer some degree of biological and clinical plausibility to the notion that high-dose intravenous vitamin C therapy may have anti-tumour effects in certain cancers. Recent findings show that only high-dose intravenous, but not oral, vitamin C therapy results in very high plasma vitamin C concentrations (e.g., 14 000 µmol/L). At these concentrations, the vitamin is toxic to some cancer cells, possibly because at these concentrations the vitamin is a pro-drug for hydrogen peroxide formation in extracellular fluid. The study examined clinical details of each cancer case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumor pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed.

The Orthomolecular Treatment of Cancer. Clinical Trial of High-Dose Ascorbic Acid Supplements in Advanced Human Cancer.

Source: Chemico-Biological Interactions, October 1974; Volume 9, Issue 4, Pages 285-315

Author: Ewan Cameron1 and Allan Campbell2

Affiliation: Department of Clinical Research, Vale of Leven District General Hospital, Dunbartonshire; Department of Medicine, Hairmyres Hospital, LanarkshireScotland,1 Institute of Orthomolecular Medicine, Menio Park, Calif.U.S.A. 2

Abstract: This study reports the clinical response of fifty consecutive advanced cancer patients to the continuous administration of large doses of ascorbic acid. It concludes that this simple and safe form of treatment is of definite value in the palliation of terminal cancer. The findings suggest that it should be employed as a standard supportive measure to reinforce established methods of treatment in the general management of earlier and more favorable cases.

The Orthomolecular Treatment of Cancer: III. Reticulum Cell Sarcoma: Double Complete Regression Induced by High-Dose Ascorbic Acid Therapy.

Source: Chemico-Biological Interactions, November 1975; Volume 11, Issue 5, , p. 387-393

Author: Ewan Cameron, Allan Campbell and Thomas Jack

Affiliation: Department of Medicine, Hairmyres Hospital, Lanarkshire, Scotland, Vale of Leven District General Hospital, Alexandria, Dumbartonshire, Scotland, the Linus Pauling Institute of Science and Medicine, Menlo Park, Calif., U.S.A.

Abstract: This study describes the response of a patient with histologically proven reticulum cell sarcoma to no treatment other than large doses of ascorbic acid. At the time of first diagnosis, the disease was widely disseminated, and a very dramatic regression of all parameters of disease activity was induced by the continuous administration of large doses of ascorbic acid. Reduction in dosage some months later coincided with reactivation of the disease process. The reinstitution of regular high-dose ascorbic acid therapy induced a second complete remission.

Supplemental Ascorbate in the Supportive treatment of Cancer: Prolongation of Survival Times in Terminal human Cancer

Source: Proceedings of the National Academy of Sciences, October 1, 1976 vol. 73 no. 10, 3685-3689

Author: E. Cameron1 and L. Pauling2

Affiliation: Vale of Leven District General Hospital, Loch Lomondside, G83 OUA, Scotland;1 Linus Pauling Institute of Science and Medicine, 2700 Sand Hill Road, Menlo Park, California 940252

Abstract: Cancer patients are significantly depleted of ascorbic acid, and in the author’s opinion this demonstrable biochemical characteristic indicates a substantially increased requirement and utilization of this substance to potentiate these various host resistance factors. This study presents the results of a clinical trial in which 100 terminal cancer patients were given supplemental ascorbate as part of their routine management. Their progress is compared to that of 1000 similar patients treated identically, but who received no supplemental ascorbate. The mean survival time is more than 4.2 times as great for the ascorbate subjects (more than 210 days) as for the controls (50 days).

Protocol for the Use of Vitamin C in the Treatment of Cancer

Source: Med Hypotheses. 1991 Nov;36(3):190-4

Author: Cameron E.

Affiliation: Linus Pauling Institute of Science and Medicine, Palo Alto, California 94306.

Abstract: A protocol for the use of vitamin C in the treatment of cancer, has been developed over a number of years in Vale of Leven Hospital, Scotland. Clinical experience has shown this protocol to be both safe and efficient, and provides general guidance to physicians unfamiliar with this therapeutic approach. It recommends that all cancer patients treated in this fashion be given an initial course of intravenous ascorbate followed by a maintenance oral dose to be continued indefinitely thereafter. The importance of continuous as opposed to intermittent administration is emphasized.

Intravenous Vitamin C as a Chemotherapy Agent: a Report on Clinical Cases.

Source: PR Health Sci J. 2004 Jun;23(2):115-8.

Author: Riordan HD, Riordan NH, Jackson JA, Casciari JJ, Hunninghake R, González MJ, Mora EM, Miranda-Massari JR, Rosario N, Rivera A.

Affiliation: Center for the Improvement of Human Functioning, RENAC Project, Wichita, KS, USA.

Abstract: A series of seven cases are presented in which intravenous vitamin C has been used as antineoplastic agent in the treatment of different types of cancers. The cancers cases reviewed are the following: Renal cell carcinoma, colorectal cancer, pancreatic cancer, Non-Hodgkin's lymphoma and breast cancer. Toxic reactions were not observed at these high doses of intravenous Vitamin C. All patients were prescreened for Glucose 6 phosphate dehydrogenase deficiency before administering intravenous vitamin C in order to prevent hemolysis.

Vitamin C and cancer revisited.

Source: Procedings of the National Academy of SciencesUSA,  2008;105(32):11037-11038.

Author: Frei B, Lawson S.

Affiliation: Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. balz.frei@oregonstate.edu

Abstract: The potential for vitamin C to destroy cancerous cells is substantial, and the regimen appears to be well tolerated, but there is still a “missing link,” Dr. Frei says. For vitamin C to act as a pro-oxidant and produce hydrogen peroxide, a protein that contains “redox-active” metal ions such as copper or iron must be present. Researchers still don’t know exactly what that metal-containing protein is, but they believe it will be the key to any anticancer effect of vitamin C.

Pharmacologic Doses of Ascorbate Act as a Pro-oxidant and Decrease Growth of Aggressive Tumor Xenografts in Mice

Source: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11105-9. Epub 2008 Aug 4

Author: Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, Khosh DB, Drisko J, Levine M.

Affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, and Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Abstract: This study shows that ascorbate at pharmacologic concentrations was a prooxidant, generating hydrogen-peroxide-dependent cytotoxicity toward a variety of cancer cells in vitro without adversely affecting normal cells. To test this action in vivo, normal oral tight control was bypassed by parenteral ascorbate administration. Moreover, a regimen of daily pharmacologic ascorbate treatment significantly decreased growth rates of ovarian (P < 0.005), pancreatic (P < 0.05), and glioblastoma (P < 0.001) tumors established in mice. These data suggest that ascorbate as a prodrug may have benefits in cancers with poor prognosis and limited therapeutic options.

Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?

Source: Journal of Translational Medicine 2011, 9:25 doi:10.1186/1479-5876-9-25

Author: Thomas E Ichim1,2, Boris Minev3, Todd Braciak2,4, Brandon Luna2, Ron Hunninghake1, Nina A Mikirova1, James A Jackson1, Michael J Gonzalez5, Jorge R Miranda-Massari6, Doru T Alexandrescu7, Constantin A Dasanu8, Vladimir Bogin2, Janis Ancans9, R Brian Stevens10, Boris Markosian2, James Koropatnick11, Chien-Shing Chen12, Neil H Riordan1,2

Affiliation: 1 Department of Orthomolecular Studies, Riordan Clinic, 3100 N Hillside, Wichita, Kansas, 67210, USA
2 Department of Regenerative Medicine, Medistem Inc, 9255 Towne Centre Drive, San Diego, California, 92121. USA
3 Department of Medicine, Moores Cancer Center, University of California San Diego, 3855 Health Sciences Dr, San Diego, California, 92121, USA
4 Department of Immunology, Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, La Jolla, California,92121, USA
5 Department of Human Development, Nutrition Program, University of Puerto Rico, Medical Sciences Campus, San Juan, 00936-5067, PR
6 Department of Pharmacy Practice, University of Puerto Rico, Medical Sciences Campus, School of Pharmacy, San Juan, 00936-5067, PR
7 Department of Experimental Studies, Georgetown Dermatology, 3301 New Mexico Ave, Washington DC, 20018, USA
8 Department of Hematology and Oncology, University of Connecticut, 115 North Eagleville Road, Hartford, Connecticut, 06269, USA
9 Department of Surgery, University of Latvia, 19 Raina Blvd, Riga, LV 1586, Latvia
10 Department of Surgery, Microbiology, and Pathology, University of Nebraska Medical Center, 42nd and Emile, Omaha, Nebraska, 86198, USA
11 Department of Microbiology and Immunology, and Department of Oncology, Lawson Health Research Institute and The University of Western Ontario, 1151 Richmond Street, London, Ontario, N2G 3M5, Canada
12 School of Medicine, Division of Hematology and Oncology, Loma Linda University,24851 Circle Dr, Loma Linda, California, 92354, USA

Abstract: The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.

Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer.

Source: Cancer Chemother Pharmacol 2013; May 14. [Epub ahead of print]

Author: Stephenson CM, Levin RD, Spector T, Lis CG.

Affiliation: Cancer Treatment Centers of America®, 2520 Elisha Ave., Zion, IL, 60099, USA.

Abstract: Purpose: This phase I clinical trial evaluated the safety, tolerability, and pharmacokinetics of high-dose intravenous (i.v.) ascorbic acid as a monotherapy in patients with advanced solid tumors refractory to standard therapy.
Methods: Five cohorts of three patients received i.v. ascorbic acid administered at 1 g/min for 4 consecutive days/week for 4 weeks, starting at 30 g/m2 in the first cohort. For subsequent cohorts, dose was increased by 20 g/m2 until a maximum tolerated dose was found.
Results: Ascorbic acid was eliminated by simple first-order kinetics. Half-life and clearance values were similar for all patients of all cohorts (2.0 ± 0.6 h, 21 ± 5 dL/h m2, respectively). C max and AUC values increased proportionately with dose between 0 and 70 g/m2, but appeared to reach maximal values at 70 g/m2 (49 mM and 220 h mM, respectively). Doses of 70, 90, and 110 g/m2 maintained levels at or above 10-20 mM for 5-6 h. All doses were well tolerated. No patient demonstrated an objective antitumor response.
Conclusions: Ascorbic acid administered i.v. at 1 g/min for 4 consecutive days/week for 4 weeks produced up to 49 mM ascorbic acid in patient's blood and was well tolerated. The recommended dose for future studies is 70-80 g/m2.

Altered deoxyribonuclease activity in cancer cells and its role in non toxic adjuvant cancer therapy with mixed vitamins C and K3.

Source: http://www.ncbi.nlm.nih.gov/pubmed/19035302

Author: Taper HS.

Affiliation: Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie Université Catholique de Louvain, Bruxelles, Belgium.

Abstract: The alterations of deoxyribonuclease DNase activity in cancer cells were the basis of the utilization of mixed vitamins C and K3 in a nontoxic, adjuvant cancer therapy. In order to localize exactly the altered activities of DNase in cancer cells, histochemical methods were utilized. The deficiency of alkaline and acid DNase activity appeared to be characteristic for non-necrotic cells of malignant human and animal tumors. This enzymatic deficiency appeared in experimental carcinogenesis before the phenotypic signs of malignancy. Tumor promoters directly reduced the activity of both DNases. The incidence of spontaneous malignant human and animal tumors appeared to be inversely proportional to the intensity of the activity of both DNases in normal cells and tissues from which these tumors were derived. The fact that alkaline and acid DNase activity was reactivated during the spontaneous and therapeutically induced necrosis of cancer cells suggests that this enzymatic deficiency of DNase activity in cancer cells was due to the action of specific inhibitors of DNases. Characteristic variations of serum alkaline DNase activity in positive responders to therapy, examined in more than 800 cancer-bearing patients, may be the basis for the development of a useful test for therapeutic prognosis and for monitoring of cancer bearing patients. Acid DNase was selectively reactivated in malignant tumor cells by vitamin C (sodium ascorbate), whereas alkaline DNase was reactivated by vitamin K3. Joint vitamin C and K3 administration produced in vitro and in vivo tumor growth inhibition, potentiation and sensitization of chemo- and/or radiotherapy and a decrease in the number of metastases in animals with experimental tumors. Joint vitamin C and K3 administration may be considered as a possible new, non-toxic, adjuvant cancer therapy, which can be easily introduced into the classic protocols of clinical cancer therapy without any supplementary risk for patients.

Vitamin C and Colon Cancer

Associations of Micronutrients with Colon Cancer Risk in African Americans and Whites: Results from the North Carolina Colon Cancer Study

Source: Cancer Epidemiology, Biomarkers & Prevention, 2003, Vol. 12, 8, pp. 747-754

Author: Satia-Abouta Jessie;1 Galanko Joseph A;2,3 Martin Christopher F.;3 Potter John D.;2 Ammerman A.;4,5 Sandler Robert S.3,6

Affiliation: Department of Nutrition, School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,1 Lineberger Comprehensive Cancer Center, Cancer Prevention and Control Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,2 School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,3 Fred Hutchinson Cancer Research Center, Cancer Prevention Research Program, Seattle, Washington 98109,4 Department of Epidemiology, University of Washington, Seattle, Washington 98105,5 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599,6

Abstract: This report describes associations of micronutrients with colon cancer risk in African Americans and whites using data from a case-control study in North Carolina. Incident cases of histologically confirmed colon cancer, age 40-80 years (n = 613), and matched controls (n = 996) were interviewed in person to elicit information on potential colon cancer risk factors. Micronutrient exposure included food sources and dietary supplements, such as vitamin C, E, beta–carotene, and calcium. These results suggest that at high intakes, micronutrients commonly found in plant and other foods (in particular, β-carotene, vitamin C, and calcium in whites and vitamins C and E in African Americans) exhibit independent associations consistent with 30-70% reductions in colon cancer risk.

Case-Control Study on Colorectal Cancer in Belgium. Preliminary Results

Source: Social and Preventive Medicine, March 1986; Volume 21, Number 2, Pages 81-82

Author: A. J. Tuyns

Affiliation: Centre international de recherche sur le cancer, 150 Cours Albert Thomas, F-69372 Lyon

Abstract: Preliminary results of a case-control study in two Belgian provinces, involving 1207 cases of colorectal cancer and 3521 population controls show that an excess risk of colon cancer is associated with low intake of calories, proteins and lipids. High intake of vitamin C, vitamin B, and fiber have a protective effect on both colon and rectal cancer. When foods were examined, most vegetables were found to have protective virtues, noticeable in all subgroups.

Vitamin D and Cancer

Vitamin D insufficiency and prognosis in chronic lymphocytic leukemia.

Source: Blood 2011; 117(5):1492-8.

Author: Shanafelt TD, Drake MT, Maurer MJ, Allmer C, Rabe KG, Slager SL, Weiner GJ, Call TG, Link BK, Zent CS, Kay NE, Hanson CA, Witzig TE, Cerhan JR.

Affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, USA.

Abstract: Vitamin D insufficiency is common globally and low levels are linked to higher cancer incidence. Although vitamin D insufficiency is related to inferior prognosis in some cancers, no data exist for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We evaluated the relationship of 25(OH)D serum levels with time-to-treatment (TTT) and overall survival (OS) in newly diagnosed CLL patients participating in a prospective cohort study (discovery cohort) and a separate cohort of previously untreated patients participating in an observational study (confirmation cohort). Of 390 CLL patients in the discovery cohort, 119 (30.5%) were 25(OH)D insufficient. After a median follow-up of 3 years, TTT and OS were shorter for 25(OH)D-insufficient patients. In the validation cohort, 61 of 153 patients (39.9%) were 25(OH)D insufficient. After a median follow-up of 9.9 years, TTT and OS were again shorter for 25(OH)D-insufficient patients. On pooled multivariable analysis of patients in both cohorts adjusting for age, sex, Rai stage, CD38 status, ZAP-70 status, immunoglobulin heavy chain variable (IGHV) gene mutation status, CD49d status, and cytogenetic abnormalities assessed by interphase fluorescent in situ hybridization testing, 25(OH)D insufficiency remained an independent predictor of TTT, although the association with OS was not significant. Conclusion: Vitamin D insufficiency is associated with inferior TTT and OS in CLL patients. Whether normalizing vitamin D levels in deficient CLL patients would improve outcome merits clinical testing.

A cohort study of vitamin D intake and melanoma risk.

Source: The journal of investigative dermatology 2009;129(7):1675-80

Author: Asgari MM, Maruti SS, Kushi LH, White E

Affiliation: Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.

Abstract: Data suggest that vitamin D intake may have chemopreventive efficacy against melanoma, but there have been no published epidemiologic studies examining the association between vitamin D intake and melanoma risk in a large prospective cohort. The authors examined whether dietary and supplemental vitamin D intake was associated with melanoma risk among 68,611 men and women who were participants of the Vitamins and Lifestyle cohort study. Participants reported dietary vitamin D intake over the past year and 10-year use of multivitamin and individual vitamin D supplements on a baseline questionnaire. After follow-up through 2006, 455 incident melanomas were identified through linkage to the Surveillance, Epidemiology, and End Results cancer registry. Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for vitamin D intake after adjustment for melanoma risk factors. Compared with the lowest quartile, we did not detect a risk reduction of melanoma in the highest quartiles of dietary vitamin D intake, 10-year average supplemental vitamin D intake, or combined dietary and supplemental intake. Conclusion: In this large prospective cohort, the authors did not find an association between vitamin D intake and melanoma risk.

Low serum levels of vitamin D in metastatic cancer patients: a case-control study.

Source: http://www.ncbi.nlm.nih.gov/pubmed/24493144

Author: Sümbül AT et al.

Affiliation: Division of Medical Oncology, Faculty of Medicine, Mustafa Kemal University, Turkey.

Abstract: Accompanying comorbidities observed during the cancer treatment usually affect the course and outcome of the therapy. Hypovitaminosis D, which is one of these conditions, is a resolvable problem, if recognized. In this study, the authors investigated whether the serum 25(OH)D levels of the patients who were presented to our outpatient clinic were different from the serum levels of the healthy population living in the same area. The study included 90 patients who were presented to the Medical Oncology outpatient clinic and 90 age, gender, body mass index and ethnic origin matched controls without a known disease, who were presented to the outpatient clinics of the Departments of Internal Diseases and Family Medicine for routine controls. Blood count tests, detailed biochemistry tests (including serum levels of Cr, Ca and P), measurement of serum 25(OH)D levels and C-reactive protein were performed in serum samples of all of the patients and controls. Mean serum levels of 25(OH)D were 13.5 ng/ml in all cancer patients, 13.1 ng/ml in the patients who were presented for adjuvant therapy, 13.8 ng/ml in the patients who were presented at metastatic stage and 18.4 ng/ml in the controls. Mean serum CRP levels were 5.4 mg/dl in the control group, 8.4 mg/dl in the adjuvant therapy group and 20.3 in the patients with metastatic disease. Generally, all cancer patients and the patients with metastatic cancer had lower serum 25(OH)D levels compared to controls, and there was an inverse correlation between serum 25(OH)D and CRP levels in patients with metastatic cancer. In metastatic cancer patients, hypovitaminosis D may be a comorbidity and it is recommended to consider during initial evaluation and follow-up.

Vitamin D and systemic cancer: is this relevant to malignant melanoma?

Source: http://www.ncbi.nlm.nih.gov/pubmed/12174089

Author: Osborne JE, Hutchinson PE.

Affiliation: Department of Dermatology, Leicester Royal Infirmary, Leicester, United Kingdom.

Abstract: 1,25-dihydroxyvitamin D3[1,25(OH)2D3] is a well-known potent regulator of cell growth and differentiation and there is recent evidence of an effect on cell death, tumour invasion and angiogenesis, which makes it a candidate agent for cancer regulation. The classical synthetic pathway of 1,25(OH)2D3 involves 25- and 1 alpha-hydroxylation of vitamin D3, in the liver and kidney, respectively, of absorbed or skin-synthesized vitamin D3. There is recent focus on the importance in growth control of local metabolism of 1,25(OH)2D3, which is a function of local tissue synthetic hydroxylases and particularly the principal catabolizing enzyme, 24-hydroxylase. The classical signalling pathway of 1,25(OH)2D3 employs the vitamin D nuclear receptor (VDR), which is a transcription factor for 1,25(OH)2D3 target genes. Effects of this pathway include inhibition of cellular growth and invasion. Cytoplasmic signalling pathways are increasingly being recognized, which similarly may regulate growth and differentiation but also apoptosis. 1,25(OH)2D3 has a major inhibitory effect on the G1/S checkpoint of the cell cycle by upregulating the cyclin dependent kinase inhibitors p27 and p21, and by inhibiting cyclin D1. Indirect mechanisms include upregulation of transforming growth factor-beta and downregulation of the epidermal growth factor receptor. 1,25(OH)2D3 may induce apoptosis either indirectly through effects on the insulin-like growth receptor and tumour necrosis factor-alpha or more directly via the Bcl-2 family system, the ceramide pathway, the death receptors (e.g. Fas) and the stress-activated protein kinase pathways (Jun N terminal kinase and p38). Inhibition of tumour invasion and metastasis potential has been demonstrated and mechanisms include inhibition of serine proteinases, metalloproteinases and angiogenesis. The lines of evidence for an effect of vitamin D3 in systemic cancer are the laboratory demonstration of relevant effects on cellular growth, differentiation, apoptosis, malignant cell invasion and metastasis; epidemiological findings of an association of the occurrence and outcome of cancers with derangements of vitamin D3/1,25(OH)2D3 and the association of functional polymorphisms of the VDR with the occurrence of certain cancers. In addition, vitamin D3 analogues are being developed as cancer chemotherapy agents. There is accumulating evidence that the vitamin D3/1,25(OH)2D3/VDR axis is similarly important in malignant melanoma (MM). MM cells express the VDR, and the antiproliferative and prodifferentiation effects of 1,25(OH)2D3 have been shown in cultured melanocytes, MM cells and MM xenografts. Recently, an inhibitory effect on the spread of MM cells has been demonstrated, low serum levels of 1,25(OH)2D3 have been reported in MM patients and the VDR polymorphisms have been shown to be associated with both the occurrence and outcome of MM. The relationship between solar irradiation and MM is more complex than for the systemic cancers. As in other cancers, there is evidence of a protective effect of vitamin D3 in MM, but ultraviolet radiation, which is a principal source of vitamin D3, is mutagenic. Further work is necessary on the influence of serum vitamin D3 levels on the occurrence and prognosis of MM, the effects of sun protection measures on serum vitamin D3 levels in temperate climates and epidemiological studies on geographical factors and skin type on the prognosis of MM. Meanwhile, it would seem mandatory to ensure an adequate vitamin D3 status if sun exposure were seriously curtailed, certainly in relation to carcinoma of breast, prostate and colon and probably also MM.