Prostate cancer in Vitamin A's Points of View

Kyle J. Norton(Draft article)

Prostate cancer, once considered a disease of aging male, now have a tendency to effect the younger generation become major concerns of governments and scientific community in South East Asian. It may be due over consumption of bad fats accompanied with unhealthy diet and life, because of  the economic prosperity over 2 decades.

Vitamin A is a general term of Vitamin A Retinol, retinal, beta-carotene, alpha-carotene, gamma-carotene, and beta-cryptoxanthin best known for its functions for vision health and antioxidant scavenger and essential for growth and differentiation of a number of cells and tissues.
Recommended intakes of vitamin A, according to  the Institute of Medicine of the National Academies (formerly National Academy of Sciences) is 600 µg daily as extremely high doses (>9000 mg) can be toxicity as causes of dry, scaly skin, fatigue, nausea, loss of appetite, bone and joint pains, headaches, etc.

1. Retinols
Retinols derived from vitamin A, most often are used in medical field in regulation of epithelial cell growth. Suggestion of serum retinol, linking to risk of prostate cancer have produced inconclusive results. Study of Serum retinol and risk of prostate cancer, showed that higher serum of retinol elevates risk of prostate cancer by by quintiles of baseline and 3-year serum retinol concentrations and by change in serum retinol levels from baseline to 3 years(1). but the study by the Erasmus University, indicated the otherwise(2)(3) with the study by Japan-Hawaii Cancer Study, Kuakini Medical Center, indicated that none of the micronutrients is strongly associated with prostate cancer risk. including serum of retinol(4).

Retinoic acid (RA), a metabolite of retinol, was found to be effective in suppression of  carcinogenesis in tumorigenic animal models for the skin, oral, lung, breast, bladder, ovarian and prostate(5). In prostate cancer LNCaP and PC3 cells, all-trans-retinoic acid (atRA) inhibited inhibited angiogenesis prostate cancer cell growth and identify retinoic acid receptor alpha as the receptor through up-regulation of retinoic acid receptor beta up-regulation and down regulation of prostate cancer cell proliferation(6). In androgen-responsive human prostate cancer cells, retinoids, the synthetic derivatives of retinol, showed to inhibit the growth of prostate caner cells and the formation and degradation of gap junctions(are ensembles of intercellular channels that permit the exchange of small growth regulatory molecules between adjoining cells), through modulation(7). In androgen receptor-negative (AR(-)) prostate cancer cells, all-trans retinoic acid (ATRA), induced the growth arrest through alteration of HOXB13(genetic variant in HOXB13 increased risk of prostate cancer vy have a 10-20-fold) expression as a result of epigenetic modifications(8). In mice study of p27(Kip1)(cell cycle suppressor gene) deficiency prostate cancer, 9-cis retinoic acid (9cRA) was found effectively in suppression of prostate cell proliferation (PECP) and increased cellular biological aging(9).

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin)
Carotenoids, plant pigments, converted to vitamin A after intake, play an important role in prevention and treatment of some diseases through it antioxidant effects.
Measured serum of Plasma carotenoids, retinol once considered as a maker for risk of prostate cancer, have produced an inconsistent result. According to the University of Oxford, there was no associations between plasma concentrations of carotenoids, retinol, or tocopherols and overall prostate cancer risk. The inverse associations of lycopene and the sum of carotenoids with the risk of advanced disease may involve a protective effect(10). Unfortunately, the study by Fred Hutchinson Cancer Research Center indicated that high serum beta-carotene concentrations were associated with increased risk for aggressive, clinically relevant prostate cancer(11) and the  Harvard Medical School showed no associated at all(12).
Epidemiological studies of carotenoids in reduced risk of prostate cancer have been inconclusive.
β-Ionone, a cyclic sesquiterpene and an end-ring analog of β-carotene, in DU145 and PC-3 cells induced apoptosis and cell cycle arrest at the G1 phase and in DU145 cells, initiated the degradation of reductase, suppressed the net growth of DU145 cells by 73%(13). Combination of  vitamin A and vitamin D, showed an effectiveness in induction of prostate cancer cells apoptosis through enhanced the expression of Bax(involved in p53-mediated apoptosis) and reduced the expression of Cyclin D1(in regulating cell cycle progression)(14). Oral administration of β-carotene (BC) inhibited the proliferation of PC-3 cells at 20 μM BC at 12 h of incubation(15). Fucoxanthin, a marine carotenoid found in brown algae, inhibited the growth of LNCap prostate cancer cells through cell cycle arrest with SAPK/JNK(involved in proliferation, apoptosis, motility) activation(16) or induces G1 arrest with GADD45 gene(growth arrest and DNA-damage inducible) expression(17). In human androgen-independent prostate carcinoma PC-3 cells, oral administration of a low or a high dose of lycopene (4 and 16 mg/kg) and a single dose of β-carotene (16 mg/kg) twice a week for 7 wk, suppressed the growth of prostate tumor cells associated with reduction of proliferation (attenuation of proliferating cell nuclear antigen expression) and with interference of the insulin-like growth factor 1 signaling (increased plasma insulin-like growth factor-binding protein-3 levels)(18).
Unfortunately, the study by the National Cancer Institute, indicated that there is not enough evidences to for a strong support for population-wide implementation of high-dose antioxidant supplementation for the prevention of prostate cancer. However, beta-carotene supplementation in men with low dietary beta-carotene intakes were associated with reduced risk of this disease(19).

Taking altogether, without going into reviews, vitamin A and its synthetic version induced apoptosis and exhibited anti proliferation of prostate cancer cell lines through cell cycle arrested and attenuated cancer progressive pathways and may be considered as potent agents in reduced risk and treatment of prostate cancer. But no doubt, certain vitamins and minerals deficiencies may play a critic role in the influence of development of prostate cancer. Over doses can lead to toxic symptoms. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Serum retinol and risk of prostate cancer by Mondul AM, Watters JL, Männistö S, Weinstein SJ, Snyder K, Virtamo J, Albanes D.(PubMed) 
(2) Serum retinol and prostate cancer.

Hayes RB, Bogdanovicz JF, Schroeder FH, De Bruijn A, Raatgever JW, Van der Maas PJ, Oishi K, Yoshida O.(PubMed)

(3) Serum retinol and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial by Schenk JM, Riboli E, Chatterjee N, Leitzmann MF, Ahn J, Albanes D, Reding DJ, Wang Y, Friesen MD, Hayes RB, Peters U.(PubMed) 

(4) Serum micronutrients and prostate cancer in Japanese Americans in Hawaii by Nomura AM, Stemmermann GN, Lee J, Craft NE.(PubMed)

(5) Retinoids and their biological effects against cancer by Alizadeh F, Bolhassani A. Khavari A, Bathaie SZ, Naji T, Bidgoli SA (PubMed)
(6) Effect of an all-trans-retinoic acid conjugate with spermine on viability of human prostate cancer and endothelial cells in vitro and angiogenesis in vivo by Vourtsis D, Lamprou M, Sadikoglou E, Giannou A, Theodorakopoulou O, Sarrou E, Magoulas GE, Bariamis SE, Athanassopoulos CM, Drainas D, Papaioannou D, Papadimitriou E.(PubMed)
(7) Retinoids regulate the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells by Kelsey L, Katoch P, Johnson KE, Batra SK, Mehta PP.(PubMed)
(8) ATRA inhibits the proliferation of DU145 prostate cancer cells through reducing the methylation level of HOXB13 gene by Liu Z, Ren G, Shangguan C, Guo L, Dong Z, Li Y, Zhang W, Zhao L, Hou P, Zhang Y, Wang X, Lu J, Huang B.(PubMed)
(9) p27(Kip1) deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process by Taylor W, Mathias A, Ali A, Ke H, Stoynev N, Shilkaitis A, Green A, Kiyokawa H, Christov K.(PubMed)
(10) Plasma carotenoids, retinol, and tocopherols and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition study by Key TJ, Appleby PN, Allen NE, Travis RC, Roddam AW, Jenab M, Egevad L, Tjønneland A, Johnsen NF, Overvad K, Linseisen J, Rohrmann S, Boeing H, Pischon T, Psaltopoulou T, Trichopoulou A, Trichopoulos D, Palli D, Vineis P, Tumino R, Berrino F, Kiemeney L, Bueno-de-Mesquita HB, Quirós JR, González CA, Martinez C, Larrañaga N, Chirlaque MD, Ardanaz E, Stattin P, Hallmans G, Khaw KT, Bingham S, Slimani N, Ferrari P, Rinaldi S, Riboli E.(PubMed)
(11) Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial by Peters U, Leitzmann MF, Chatterjee N, Wang Y, Albanes D, Gelmann EP, Friesen MD, Riboli E, Hayes RB.(PubMed)

(12) Intake of carotenoids and retinol in relation to risk of prostate cancer by Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett WC.(PubMed)
(13) β-ionone induces cell cycle arrest and apoptosis in human prostate tumor cells by Jones S, Fernandes NV, Yeganehjoo H, Katuru R, Qu H, Yu Z, Mo H.(PubMed)
(14) Synergistic effect and mechanism of vitamin A and vitamin D on inducing apoptosis of prostate cancer cells by Sha J, Pan J, Ping P, Xuan H, Li D, Bo J, Liu D, Huang Y.(PubMed)
(15) Diverse effects of β-carotene on secretion and expression of VEGF in human hepatocarcinoma and prostate tumor cells by Chen HY, Huang SM, Yang CM, Hu ML.(PubMed)
(16) Fucoxanthin induces GADD45A expression and G1 arrest with SAPK/JNK activation in LNCap human prostate cancer cells by Satomi Y.(PubMed)
(17) Fucoxanthin, a natural carotenoid, induces G1 arrest and GADD45 gene expression in human cancer cells by Yoshiko S, Hoyoku N.(PubMed)
(18) Growth inhibitory efficacy of lycopene and β-carotene against androgen-independent prostate tumor cells xenografted in nude mice by Yang CM, Yen YT, Huang CS, Hu ML.(PubMed)
 (19) Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk by Kirsh VA, Hayes RB, Mayne ST, Chatterjee N, Subar AF, Dixon LB, Albanes D, Andriole GL, Urban DA, Peters U; PLCO Trial.(PubMed)

Breast cancer in Vitamin B6's Points of view

 By Kyle J. Norton (Draft article)

Vitamin B5, also known as Pantothenic acid or pantothenate is a water soluble vitamin found abundantly in avocado, banana, dried beans, meat, nuts and whole grains cereals etc., with functions of amino acid, glucose and lipid metabolism, neurotransmitter synthesishistamine synthesis,  hemoglobin synthesis and function gene expression.
Epidemiological studies focusing vitamin B6 in reduced risk of breast cancer have produced conflict results. But the widespread of breast cancer has caused many concerns in the world leaders and scientific community. Every year, over 250,000 new cases of breast cancer were expected to be diagnosed in women in the U.S. alone and the risk of getting invasive breast cancer during life time of a women is 1/8.

In postmenopausal women, vitamin B6(Serum pyridoxal 5'-phosphate (PLP, active form of vitamin B6) levels) might be inversely associated with breast cancer risk(1)(1a). But in a case-control study in Brazilian women, MTHFR polymorphisms and dietary intake of  vitamin B6 had no overall association with breast cancer risk(2). Study of the Chinese women, genetic mutation of MTHFR and vitamin B 6 were associated with risk of breast cancer(3). Dietary intake of one-carbon nutrients, particularly folate, vitamin B(2) (riboflavin), vitamin B(6) , vitamin B(12) , and choline also linked to the risk of cancers of the colon and breast in both human and animal studies and maternal intake of these nutrients during gestation may also have an impact on the risk of cancer in offspring later in life(3a). In Japanese women study, neither dietary intake of folate, vitamin B2, vitamin B6, or vitamin B12 nor polymorphisms of MTHFR or MTR genes were significantly associated with breast cancer risk(4). In  estrogen receptor (ER) and progesterone receptor (PR) breast cancers, dietary vitamin B6 intakes were inversely associated with breast cancer risk, regardless to ER and/or PR status(5). In postmenopausal breast cancer study, women with highest quartile range of plasma PLP concentrations are associated to 30% reduced risk of invasive breast cancer compared with the women in the lowest PLP quartile(6)(7)(8). In rodent models, high dose of B(6) also suppressed cell proliferation and induced apoptosis of human breast adenocarcinoma MCF-7 cells through induction of IGFBP-3 by PN then by a p53-specific inhibitor(8)

Taking all together, The effective of vitamin B6, in reduced risk of breast cancer is deemed controversial. But no doubt, certain vitamins and minerals deficiencies may play a critic role in the influence of development of breast cancer. Over doses may induced the symptoms of difficulty coordinating movement, numbness, sensory changes, etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Dietary intake of folate, vitamin B6, and vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Brazilian women by Ma E, Iwasaki M, Junko I, Hamada GS, Nishimoto IN, Carvalho SM, Motola J Jr, Laginha FM, Tsugane S.(PubMed)
(1a) Dietary folate, vitamin B6, vitamin B12 and methionine intake and the risk of breast cancer by oestrogen and progesterone receptor status by Zhang CX, Ho SC, Chen YM, Lin FY, Fu JH, Cheng SZ.(PubMed)
(2) Association of dietary intake of folate, vitamin B6 and B12 and MTHFR genotype with breast cancer risk by Liu Y, Zhou LS, Xu XM, Deng LQ, Xiao QK.(PubMed)
(3) Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan by Ma E, Iwasaki M, Kobayashi M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S.(PubMed)
(3a) Maternal one-carbon nutrient intake and cancer risk in offspring by Ciappio ED, Mason JB, Crott JW.(PubMed)
(4) Dietary folate, vitamin B6, vitamin B12 and methionine intake and the risk of breast cancer by oestrogen and progesterone receptor status by Zhang CX, Ho SC, Chen YM, Lin FY, Fu JH, Cheng SZ(PubMed)
(5) Prediagnostic plasma pyridoxal 5'-phosphate (vitamin b6) levels and invasive breast carcinoma risk: the multiethnic cohort by Lurie G, Wilkens LR, Shvetsov YB, Ollberding NJ, Franke AA, Henderson BE, Kolonel LN, Goodman MT.(PubMed)
(6) Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women by Lin J, Lee IM, Cook NR, Selhub J, Manson JE, Buring JE, Zhang SM(PubMed)
(7) Association of vitamin B6, vitamin B12 and methionine with risk of breast cancer: a dose-response meta-analysis by Wu W, Kang S, Zhang D.(PubMed)
(8) High dose of pyridoxine induces IGFBP-3 mRNA expression in MCF-7 cells and its induction is inhibited by the p53-specific inhibitor pifithrin-α by Nakari M, Kanouchi H, Oka T.(PubMed)

Breast cancer in Vitamin E's Point of View

Kyle J. Norton(Draft Article)

Epidemiological study, linking vitamin E in reduced risk of breast cancer focused on variant α-tocopherol with inconsistent results. Researches in γ-tocopherol,  δ-tocopherol, have shown a promising potential.  In recent study, the variants showed a  a greater ability in reducing inflammation, cell proliferation, and inhibited the development of mammary hyperplasia and tumorigenesis(1)(1a)(1b)
 Vitamin E, a fat soluble vitamin, consisting eight different variants (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) with varying levels of biological activity(2), found abundantly in corn oil, soybean oil, margarine, wheat germ oil, sunflower,safflower oils, etc. plays an important role in neurological functions and inhibition of platelet aggregation, regulation of enzymatic activity, free radical scavenger, etc..
A  cohort study from the Breast Cancer Serum Bank in Columbia, with free of cancer sample blood  donated blood to this bank did not found any evidence for protective effects of  alpha-tocopherol for breast cancer(3). Observation of her-2/neu indicated the correlation with Her2/neu receptor and reduced TAP expression found in  breast cancer stage and nodal stage in paired normal and cancerous breast tissue samples, α-tocopheryl succinate (α-TOS), a synthetic derivative of α-tocopherol, enhanced the efficacy of doxorubicin resulting in a reduction in cell viability in breast cancers(3a). In MCF-7 breast cancer cell line, dl-alpha-tocopherol showed evidence of a general inhibition of cell proliferation(3b). In HER-2/neu breast cancer cells and in comparison of the  anticancer effect of alpha-, gamma-, and delta-tocotrienols with alpha-tocopheryl succinate (alpha-TOS), the non-alpha form of T3 is more potent in inhibition of cancer activity than the synthetic VE-derivative alpha-TOS, possibly through the mitochondrial pathway, and the expression of senescent-like growth arrest markers(which provides a possible marker for the process) as p53tumor antigen), p21(regulator of cell cycle progression at G₁ and S phase), , and p16(multiple tumor suppressor 1)(3c). Delta-tocotrienol, isolated from the tocotrienol-rich fraction of palm oil, showed a positive effective against metastatic breast cancers(3d). Other in the study of estrogen-responsive MCF7 cells and the estrogen-nonresponsive MDA-MB-435 cells, RRR-alpha-, beta-, gamma-and delta-tocotrienols and and RRR-delta-tocopherol induced MDA-MB-435 cells to undergo apoptosis, with the exception of RRR-delta-tocopherol, the tocopherols (alpha, beta, and gamma) and the acetate derivative of RRR-alpha-tocopherol (RRR-alpha-tocopheryl acetate)(3e).

In aggressive triple negative MDA-MB-231 cells and oestrogen-dependent MCF-7 cells, tocotrienol-rich fraction (TRF) and a tocotrienol-enriched fraction (TEF) isolated from palm oil showed a positive effect in induction of anti-proliferation and apoptosis through DNA repair protein and NF-κB, an apoptotic cell death signalling pathway(4). In HER-2/neu-overexpressing human SKBR3 and murine TUBO breast cancer cells, vitamin E form δ-tocotrienol (δ-T3) possessed significantly high cytotoxic and apoptotic activity in SKBR3 cells than other facttions of vitamin E, through  mitochondrial destabilization, energy failure, and unbalanced activity of stress/survival MAPKs, namely p38 ((highly expressed in aggressive and invasive breast cancers) and ERK1/2(cell regulation) pathways(5). In human MDA-mB-231 breast cancer cells, delta-tocotrienol exerted its anti cancer effect trough suppression of site-specific Rb phosphorylation and mediation of  by the loss of cyclin D1(6). In estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF-7 human breast cancer cells, vitamin E succinate (VES) or dl-alpha-tocopherol (refers to eight naturally occurring and synthetic tocopherols and tocotrienols and their acetate and succinate derivatives), induced apoptosis involving up-regulation of TGF-beta receptor II (tumor suppressor gene) expression and TGF-beta-(cell prcess), Fas- (associated with the induction of apoptosis) and JNK- (cellular apoptosis) signaling pathways(7). These results indicated that tocotrienols exerted directly inhibitory effects on the growth of breast cancer cells irrespective of estrogen receptor status, not via an estrogen receptor-mediated pathway(8).
Also in  human (MCF-7 and MDA-MD-231) mammary tumor cells lines, γ-tocotrienol induced apoptosis through induction of autophagy with evidences of the presence of relatively large increase in the accumulation of monodansylcadaverine (MDC)-labeled vacuoles, a marker of autophagosome formation(9). In neoplastic(gene modification)  +SA(high malignance) mammary epithelial cells, treatment with 4 microM gamma-tocotrienol, a dose that inhibited +SA cell growth by more than 50% compared with that of untreated control cells, decreased intracellular levels of activated PI3K/Akt (anti-apoptosis and increased cell proliferation) pathway(10). On mouse (+SA) and human (MCF-7, and MDA-MB-231) mammary cancer cell lines, Combined γ-tocotrienol and SU11274 (Met inhibitor) treatment resulted in synergistic inhibition through reduction in Akt (multiple cellular processes) STAT1/5 (activator of transcription 1,5 )and NFκB(a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis) activation and corresponding blockade in epithelial-to-mesenchymal transition( a process by which epithelial cells lose their cell polarity and cell-cell adhesion and start a the initiation of metastasis for cancer progression.), as indicated by increased expression of E-cadherin, β-catenin, and cytokeratins 8/18 (epithelial markers) and corresponding reduction in vimentin (mesenchymal marker) and reduction in cancer cell motility(11). In other study, treatment of gamma-tocopherol (γT) and gamma-tocotrienol (γT3) in human breast cancer cell lines, induced apoptosis via de novo ceramide synthesis(key molecules in cellular life and death decisions and the precursors to complex sphingolipids found in membranes) dependent activation of JNK/CHOP((C/EBP homologous protein)/DR5 pro-apoptotic signaling(12) and in γ-tocopherol (γT) alone,  the variant showed to suppress inflammatory markers, inhibited E2 -induced cell proliferation, and up regulated PPARγ(regulation of cellular differentiation, development, and metabolism) and Nrf2 (antioxidant response pathway)expression in mammary hyperplasia(13) or  modulated ER stress signaling targeting ATF3(activating transcription factor 3, involved in the complex process of cellular stress response)  in breast cancer cells(14). In HER2/neu, vitamin E analog namely alpha-tocopheryloxyacetic acid, inhibited the proliferation of kills both HER2/neu positive and HER2/neu negative breast cancer cells with less toxic than existing chemotherapeutic drugs when used in combination with HER2/neu antibody(15).

Taken the evidences of the effects of tocotrienols, dietary vitamin E or vitamin E supplement may provide significant health benefits in the reduced risk and prevention and/or treatment of breast cancer when used either alone or in combination with other anticancer agents(16). 
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References
(1) Chemopreventive activity of vitamin E in breast cancer: a focus on γ- and δ-tocopherol by Smolarek AK, Suh N.(PubMed)
(1a) Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells by Sylvester PW, Shah SJ.(PubMed)
(1b) Dietary administration of δ- and γ-tocopherol inhibits tumorigenesis in the animal model of estrogen receptor-positive, but not HER-2 breast cancer by Smolarek AK, So JY, Burgess B, Kong AN, Reuhl K, Lin Y, Shih WJ, Li G, Lee MJ, Chen YK, Yang CS, Suh N.(PubMed)
(2) Traber MG. Vitamin E. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins R, eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore, MD: Lippincott Williams & Wilkins, 2006;396-411.
(3) Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States) by Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, Stephenson HE Jr(PubMed)
(3a) Alteration of α-tocopherol-associated protein (TAP) expression in human breast epithelial cells during breast cancer development by Tam KW, Ho CT, Lee WJ, Tu SH, Huang CS, Chen CS, Lee CH, Wu CH, Ho YS.(PubMed)
(3b) dl-alpha-tocopherol induces apoptosis in erythroleukemia, prostate, and breast cancer cells by Sigounas G, Anagnostou A, Steiner M.(PubMed)
(3c) Gamma- and delta-tocotrienols exert a more potent anticancer effect than alpha-tocopheryl succinate on breast cancer cell lines irrespective of HER-2/neu expression by Pierpaoli E, Viola V, Pilolli F, Piroddi M, Galli F, Provinciali M.(PubMed)
(3d) Synthesis of fluorescent analogues of the anticancer natural products 4-hydroxyphenylmethylene hydantoin and delta-tocotrienol by Mudit M, Behery FA, Wali VB, Sylvester PW, El Sayed KA.(PubMed)
(3e) Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols by Yu W, Simmons-Menchaca M, Gapor A, Sanders BG, Kline K.(PubMed).
(4) Tocotrienols promote apoptosis in human breast cancer cells by inducing poly(ADP-ribose) polymerase cleavage and inhibiting nuclear factor kappa-B activity by Loganathan R, Selvaduray KR, Nesaretnam K, Radhakrishnan AK.(PubMed)
(5) Mitochondrial-dependent anticancer activity of δ-tocotrienol and its synthetic derivatives in HER-2/neu overexpressing breast adenocarcinoma cells by Viola V, Ciffolilli S, Legnaioli S, Piroddi M, Betti M, Mazzini F, Pierpaoli E, Provinciali M, Galli F.(PubMed)
(6) Growth inhibition of human MDA-mB-231 breast cancer cells by delta-tocotrienol is associated with loss of cyclin D1/CDK4 expression and accompanying changes in the state of phosphorylation of the retinoblastoma tumor suppressor gene product by Elangovan S, Hsieh TC, Wu JM.(PubMed)
(7) Pro-apoptotic mechanisms of action of a novel vitamin E analog (alpha-TEA) and a naturally occurring form of vitamin E (delta-tocotrienol) in MDA-MB-435 human breast cancer cells by Shun MC, Yu W, Gapor A, Parsons R, Atkinson J, Sanders BG, Kline K.(PubMed)
(8) Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status by Nesaretnam K, Stephen R, Dils R, Darbre P.(PubMed)
(9)γ-Tocotrienol-induced autophagy in malignant mammary cancer cells by Tiwari RV, Parajuli P, Sylvester PW.(PubMed)
(10) Gamma-tocotrienol inhibits neoplastic mammary epithelial cell proliferation by decreasing Akt and nuclear factor kappaB activity by Shah SJ, Sylvester PW.(PubMed)
(11) Combined γ-tocotrienol and Met inhibitor treatment suppresses mammary cancer cell proliferation, epithelial-to-mesenchymal transition and migration by Ayoub NM, Akl MR, Sylvester PW.(PubMed)
(12) Involvement of de novo ceramide synthesis in gamma-tocopherol and gamma-tocotrienol-induced apoptosis in human breast cancer cells by Gopalan A, Yu W, Jiang Q, Jang Y, Sanders BG, Kline K.(12)
(13) Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia by Smolarek AK, So JY, Thomas PE, Lee HJ, Paul S, Dombrowski A, Wang CX, Saw CL, Khor TO, Kong AN, Reuhl K, Lee MJ, Yang CS, Suh N.(PubMed)
(14) Gamma-tocotrienol induced apoptosis is associated with unfolded protein response in human breast cancer cells by Patacsil D, Tran AT, Cho YS, Suy S, Saenz F, Malyukova I, Ressom H, Collins SP, Clarke R, Kumar D.(PubMed)
(15) The vitamin E analog, alpha-tocopheryloxyacetic acid enhances the anti-tumor activity of trastuzumab against HER2/neu-expressing breast cancer by Hahn T, Bradley-Dunlop DJ, Hurley LH, Von-Hoff D, Gately S, Mary DL, Lu H, Penichet ML, Besselsen DG, Cole BB, Meeuwsen T, Walker E, Akporiaye ET.(PubMed)
(16) Potential role of tocotrienols in the treatment and prevention of breast cancer by Sylvester PW, Akl MR, Malaviya A, Parajuli P, Ananthula S, Tiwari RV, Ayoub NM.(PubMed)

PCOs Diets

 Kyle J. Norton (Draft article)

Approximately half of women with polycystic ovary syndrome (PCOs) are obese and overweight. Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5% to 10% of women worldwide.
1. High Protein Diet with Low-Glycemic-Load Hypocaloric Diet
Diet with 30% of protein is now considered reasonable, high protein diet is the term reserved for consumption of 50%.
Suggestions of linking High Protein Diet with Low-Glycemic-Load Hypocaloric Diet and PCOs to control and combat in polycystic ovary syndrome (PCOS) have drawn attention in scientific community over last decade. It may be due to its effect in reduced appetites and calorie intake. But epidemiological studies focusing the benefit of diets in treating obese and overweight patients have produced an inclusive results. The National Nutrition and Food Technology Research Institute showed that both composition of hypocaloric and hypocaloric diet lead to significantly led to reduced body weight and androgen levels.  Compared with a conventional diet, the combination of high-protein and low-glycemic-load foods and Hypocaloric diett also found to be effective in enhanced insulin sensitivity and decreased hsCRP level when (1). But the alternation of metabolic rate of hypocaloric diet  in glucose utilization and decreased antioxidant defenses, in some case may result in life-threatening(8a).

2. Hypocaloric diet
 Comparison with Metformin in the same subjects, hypocaloric(low calories) diet showed an reduction of 5-10% of weight on markers of insulin resistance with  equal efficacy with Metformin in decreasing serum hs-CRP levels(2) and improving inflammatory biomarkers and adipokines independently of dietary composition(3). In a 20 weeks of a high-protein energy-restricted diet to evaluate the Markers of endothelial dysfunction, including elevated markers of endothelial dysfunction, presented in overweight and obese women with polycystic ovary syndrome, showed an significant weight loss, improved testosterone, sex hormone-binding globulin and the free androgen index (FAI) and insulin resistance(4). Sibutramine(the hydrochloride monohydrate salt) removed from the market because of the concerns of risk of heart attack and stroke, in a comparison test with hypocaloric diet, showed a significant weight loss in overweight and obese women with PCOS and improvement in hyperandrogenemia and insulin sensitivity after 6 months of treatment(5). Clomiphene citrate (CC) used comjuction with hypocaloric diet with structured exercise training (SET) after 6 weeks in overweight and obese CC-resistant PCOS patients, enhancing the probability of ovulation under CC treatment, through a a significant improvement in clinical and biochemical androgen and insulin sensitivity indexes(6).
Comparison of  a hypocaloric low-fat diet with those of a very low carbohydrate diet, showed the positive effects in both diets in significant improvements in BMI, WC, and menstrual function and induced weight loss through targeting both the menstrual dysfunction and risk factors for long-term morbidity associated with PCOS in adolescents(7). Short-term hypocaloric diet including high protein (HP: 30% protein, 40% carbohydrate, and 30% fat) or high carbohydrate (HC: 15% protein, 55% carbohydrate, and 30% fat) showed a significant weight loss reduction and  improvement in their reproductive and metabolic abnormalities with no increased benefit to a high-protein diet(8).
Some researchers suggested that Hypocaloric (low-calorie) diets can alter your metabolic rate in glucose utilization and decreased antioxidant defenses, in some case may result in life-threatening(8a).

3. Low-carbohydrate diet
  A high-fat, adequate-protein, low-carbohydrate diet  used in medicine primarily to treat difficult-to-control (refractory) epilepsy in children with purpose to induce the body to burn fat other than carbohydrate. In a women 24 weeks study with  limit carbohydrate intake to 20 grams or less per day for women diagnosed with PCOs, showed non-significant decreases in insulin, glucose, testosterone, HgbA1c, triglyceride, and perceived body hair but improvement in weight, percent free testosterone, LH/FSH ratio, and fasting insulin in women with obesity(9). According to the University of Padova study, "Epidemiological studies over last decade or so has provided evidence of the therapeutic potential of ketogenic diets in many pathological conditions, such as diabetes, polycystic ovary syndrome, acne, neurological diseases, cancer and the amelioration of respiratory and cardiovascular disease risk factors"(10). Some researcher insisted that the presence of high levels of insulin in the blood causes unnecessary water retention in the body(10a), the diet may produce a short term effect through eliminating excess body fat but may cause to cause dehydration as an early-onset complication(10b)

4. Low glycemic index diet
Glycemic index diet originally is developed to help improve blood sugar control in diabetes by choosing foods Low-GI foods (55 and under) for steadier rise in blood sugar.In a Twenty-six participants recruited at baseline, 22 commenced and 21 participants completed the low-GI dietary intervention phase, low glycemic diet improved insulin sensitivity, changes of lipids(11). Comparison of low glycemic index with a conventional healthy diet in overweight and obese premenopausal women, low glycemic index attendants showed to improve more in glucose tolerance through oral-glucose-tolerance test (ISI(OGTT)), menstrual cyclicity, with serum fibrinogen concentrations significant differences between diets(12). Researchers also suggested that longer term compliance needs more evaluation in subsequent studies to reduced long term health risks to women with PCOS on a low GI diet(13). In comparison of low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus, some researchers suggested that The diet containing fewer carbohydrates, the low-carbohydrate, ketogenic diet, was more effective for improving glycemic control than the low glycemic diet(12a).

5. High-protein diet
High-protein diet is a diet mostly recommended for people who want to build muscle and lose fat. A comparison of a high protein (HP) and a normal protein (NP) diet on patients with polycystic ovary syndrome (PCOS) in 8-week randomized trial, showed a significantly reduced body weight, body mass index (BMI), waist circumference, percent of body fat,  decreased total testosterone also decreased in PCOS and sum of trunk skinfolds decreased in both diets(14).  In fact, increased dietary protein-to-carbohydrate ratios showed no differences in testosterone, sex hormone-binding globulin, and blood lipids between the groups after 6 months, but adjustment for weight changes led to significantly lower testosterone concentrations in the standard-protein (SP) diet group, according to the University of Copenhagen(15). Unfortunately, some studies showed that consumption of HP diets may cause alterations in renal health status and some metabolic parameters(15a) and reduce the level of osteocalcin(15b)

7. High monounsaturated fat diet
High monounsaturated fat diet is a diet high in monounsaturated fatty acids (HMUFA) by replacing them for daily intake of bad fat. In a comparison of Carbohydrate-restricted diets high in either monounsaturated fat or protein, showed that magnitude of weight loss was smaller in the LF-HP group than in the HF-SP(16). The Mediterranean diet, a High monounsaturated fat diet is characterized by a high intake of olive oil, plant products, fish and seafood; a low intake of dairies, meat and meat products; and a moderate ethanol intake, but unfortunately, exploring the relationship between the Mediterranean diet and overweight/obesity is complex with inclusive results, some studies showed a significantly related to less overweight/obesity or more weight loss but many found no evidence of this association(16a).

8. Low fat diet 
Low fat diet restricts consumption of fat, stressing foods high in carbohydrates, mostly recommended to patients with some gallbladder conditions. Comparison of hormonal and metabolic markers after a high-fat, Western meal versus a low-fat, high-fiber meal in women with polycystic ovary syndrome, showed a reduction of free testosterone within 2 hours after both meals, however, the levels of testosterone remained below premeal values for 4 hours after the isocaloric low-fat, high-fiber meal (HIFIB) meal and 6 hours after the a high-fat, Western meal (HIFAT) meal. Levels of glucose was higher for 1 hour after the HIFIB meal compared with the HIFAT meal. DHEAS decreased 8%-10% within 2-3 hours after both meals, then increased during the remainder of the study period. Cortisol decreased during the 6-hour period after both meals(17). There is a suggestion of individuals on a low-fat vegan in ensured adequate intakes of  of vitamin D, vitamin K, folic acid, calcium, magnesium, zinc, vitamin B12, phosphorous, and selenium(17a).

Taking all together, there were subtle differences but correlation between diets, a monounsaturated fat-enriched diet greater weight loss, a low-glycemic index diet enhanced menstrual regularity, a high-carbohydrate diet increased free androgen index, a low-carbohydrate or low-glycemic index dietgreater reductions in insulin resistance, fibrinogen, total testosterone, and high-density lipoprotein cholesterol, a low-glycemic index diet improved quality of life, a high-protein diet.improved depression and self-esteem for a high-protein diet. Maximize weight loss control is important for women with PCOS regardless of dietary composition in the majority of studies and should be targeted in all overweight women with PCOS through reducing caloric intake with adequate nutritional intake and healthy food choices irrespective of diet composition(18).
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References
(1) Beneficial effects of a high-protein, low-glycemic-load hypocaloric diet in overweight and obese women with polycystic ovary syndrome: a randomized controlled intervention study by Mehrabani HH, Salehpour S, Amiri Z, Farahani SJ, Meyer BJ, Tahbaz F.(PubMed)
(2) Effect of metformin compared with hypocaloric diet on serum C-reactive protein level and insulin resistance in obese and overweight women with polycystic ovary syndrome by Esfahanian F, Zamani MM, Heshmat R, Moini nia F.(PubMed)
(3) Effect of a low-fat versus a low-gycemic-load diet on inflammatory biomarker and adipokine concentrations by Heggen E, Klemsdal TO, Haugen F, Holme I, Tonstad S.(PubMed)
(4) The effect of diet and exercise on markers of endothelial function in overweight and obese women with polycystic ovary eby Thomson RL, Brinkworth GD, Noakes M, Clifton PM, Norman RJ, Buckley JD.(PubMed)
(5) Effect of hypocaloric diet plus sibutramine treatment on hormonal and metabolic features in overweight and obese women with polycystic ovary syndrome: a randomized, 24-week study by Florakis D, Diamanti-Kandarakis E, Katsikis I, Nassis GP, Karkanaki A, Georgopoulos N, Panidis D.(PubMed)
(6) Six weeks of structured exercise training and hypocaloric diet increases the probability of ovulation after clomiphene citrate in overweight and obese patients with polycystic ovary syndrome: a randomized controlled trial by Palomba S, Falbo A, Giallauria F, Russo T, Rocca M, Tolino A, Zullo F, Orio F.(PubMed)
(7) Effect of weight loss on menstrual function in adolescents with polycystic ovary syndrome by Ornstein RM, Copperman NM, Jacobson MS.(PubMed)
(8) A randomized trial of the effects of two types of short-term hypocaloric diets on weight loss in women with polycystic ovary syndrome by Stamets K, Taylor DS, Kunselman A, Demers LM, Pelkman CL, Legro RS.(PubMed)
(8a) Toxicity of hypercaloric diet and monosodium glutamate: oxidative stress and metabolic shifting in hepatic tissue by Diniz YS, Fernandes AA, Campos KE, Mani F, Ribas BO, Novelli EL.(PubMed)
(9) The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study by Mavropoulos JC, Yancy WS, Hepburn J, Westman EC.(PubMed)
(10) Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets by Paoli A, Rubini A, Volek JS, Grimaldi KA.(PubMed)
(1a) Eades, M. (1995) The Protein Power Lifeplan, Warner Books.
(1b) Early- and Late-onset Complications of the Ketogenic Diet for Intractable Epilepsy by Hoon Chul Kang¹, Da Eun Chung¹, Dong Wook Kim², Heung Dong Kim (Wily online library)(11) An isocaloric low glycemic index diet improves insulin sensitivity in women with polycystic ovary syndrome by Barr S, Reeves S, Sharp K, Jeanes YM.(PubMed)
(12) Effect of a low glycemic index compared with a conventional healthy diet on polycystic ovary syndrome by Marsh KA, Steinbeck KS, Atkinson FS, Petocz P, Brand-Miller JC.(PubMed)
(12a) The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus by Eric C Westman^1*, William S Yancy¹², John C Mavropoulos¹, Megan Marquart¹ and Jennifer R McDuffie(Nutrition&Metabolism)
(13) Evaluating compliance to a low glycaemic index (GI) diet in women with polycystic ovary syndrome (PCOS) by Egan N, Read A, Riley P, Atiomo W.(PubMed)
(14) Effect of high-protein or normal-protein diet on weight loss, body composition, hormone, and metabolic profile in southern Brazilian women with polycystic ovary syndrome: a randomized study by Toscani MK, Mario FM, Radavelli-Bagatini S, Wiltgen D, Matos MC, Spritzer PM.(PubMed)
(15) Carbohydrate-restricted diets high in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids by Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Foster P, Clifton PM.(PubMed)
(15a) Effects of high-whey-protein intake and resistance training on renal, bone and metabolic parameters in rats by Aparicio VA, Nebot E, Porres JM, Ortega FB, Heredia JM, López-Jurado M, Ramírez PA.(PubMed)
(15b) Effects of dietary protein and glycaemic index on biomarkers of bone turnover in children by Dalskov SM¹, Müller M², Ritz C¹, Damsgaard CT¹, Papadaki A³, Saris WH⁴, Astrup A¹, Michaelsen KF¹, Mølgaard C¹; on behalf of DiOGenes(PubMed)
(16) Carbohydrate-restricted diets high in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids by Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Foster P, Clifton PM.(PubMed)
(16a) Obesity and the Mediterranean diet: a systematic review of observational and intervention studies by Buckland G, Bach A, Serra-Majem L.(PubMed)

(17) Comparison of hormonal and metabolic markers after a high-fat, Western meal versus a low-fat, high-fiber meal in women with polycystic ovary syndrome by Katcher HI, Kunselman AR, Dmitrovic R, Demers LM, Gnatuk CL, Kris-Etherton PM, Legro RS.(PubMed)
(17a) Effects of a low-fat vegan diet and a Step II diet on macro- and micronutrient intakes in overweight postmenopausal women by Turner-McGrievy GM, Barnard ND, Scialli AR, Lanou AJ.(PubMed)

(18) Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines by Moran LJ, Ko H, Misso M, Marsh K, Noakes M, Talbot M, Frearson M, Thondan M, Stepto N, Teede HJ.(PubMed)

Breast cancer in Vitamin B3's Points of view

 By Kyle J. Norton (Draft Article)

Niacin, is also known as vitamin B3, nicotinic acid, an organic compound with the formula
C6H5NO2. It is best known for its effects in lowering cholesterol and triglycerides and removing toxic from our body and promoting production of steroid hormones.
Epidemiological studies, focused in niacin in reduced risk of breast cancer have produced conflict results. In human breast cancer cell, combination of niacin and butyrate induced apoptosis, through activation of GPR109A, a G-protein-coupled receptor in inhibition of genes, involved in cell survival and anti-apoptotic signaling(1). But in the study of breast cancer risk among Chinese women, niacin was found to be associated with ER+/PR+ breast cancer risk depending to the highest vs. lowest quartile of intake in premenopausal women(2). Unfortunately, some researchers indicated that regardless to the doses, even Mega-dose vitamins and minerals did not improve the breast cancer-specific survival and disease-free survival times in breast cancer patients(2a).

The study of potent antioxidant Niacin (CoRN), co administration with Tamoxifen (TAM) showed favorable impact on various blood chemistry profiles and may be considered as a co-administrating antioxidants with conventional chemotherapy but large scale randomized studies over a longer time span are required to ascertain the safety and efficacy(3).
In tumour angiogenesis, the co administrations also decreased the levels of pro-angiogenic factors which reduced the tumor burden in protection from cancer metastases and recurrence(4). Oral administration of daily supplement of 100 mg co-enzyme Q10, 10 mg riboflavin and 50 mg niacin (CoRN), one dosage per d along with 10 mg tamoxifen twice per day in breast caner patients showed to reduce tumor burden  by significant increase in poly(ADP-ribose polymerase levels(Differentiation, proliferation, and tumor transformation and and Normal or abnormal recovery from DNA damage)) and disappearance of RASSF1A(involved in early tumorigenesis) DNA methylation patterns(5). In postmenopausal women with breast cancer, the above combination significantly increased the AO(antioxidants) status, while decreasing lipid and lipid peroxides(free radical)(6).

Niacin is found effectively in reduced risk of breast cancer, combination with other vitamins and Tamoxifen (TAM) show to provide protection and management in the process of breast cancer treatments, through exhibition of antioxidants status and decreased free radical expression. Please make sure to follow the guideline of the Institute of Medicine of the National Academies. Although unlikely, overdoses of vitamin B3 may induce symptoms of severe skin flushing combined with dizziness, rapid heartbeat, itching, nausea, vomiting, abdominal pain, etc.

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References
(1) The niacin/butyrate receptor GPR109A suppresses mammary tumorigenesis by inhibiting cell survival by Elangovan S, Pathania R, Ramachandran S, Ananth S, Padia RN, Lan L, Singh N, Martin PM, Hawthorn L, Prasad PD, Ganapathy V, Thangaraju M.(PubMed)
(2) Dietary B vitamin and methionine intakes and breast cancer risk among Chinese women by Shrubsole MJ, Shu XO, Li HL, Cai H, Yang G, Gao YT, Gao J, Zheng W.(PubMed)
(2a) Mega-dose vitamins and minerals in the treatment of non-metastatic breast cancer: an historical cohort study by Lesperance ML, Olivotto IA, Forde N, Zhao Y, Speers C, Foster H, Tsao M, MacPherson N, Hoffer A.(PubMed)
(3) Effect of Coenzyme Q(10), Riboflavin and Niacin on Tamoxifen treated postmenopausal breast cancer women with special reference to blood chemistry profiles by Yuvaraj S, Premkumar VG, Shanthi P, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)
(4) Anti-angiogenic potential of CoenzymeQ10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy by Premkumar VG, Yuvaraj S, Sathish S, Shanthi P, Sachdanandam P.(PubMed)
(5) Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy by Premkumar VG, Yuvaraj S, Shanthi P, Sachdanandam P.(PubMed)
(6) Augmented antioxidant status in Tamoxifen treated postmenopausal women with breast cancer on co-administration with Coenzyme Q10, Niacin and Riboflavin by Yuvaraj S, Premkumar VG, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)

Breast cancer in Vitamin B2's Point of view

 Kyle J. Norton(Draft article)

Vitamin B2 also known Riboflavin is a water-soluble, yellow-orange organic compound found abundantly in milk, meat, eggs, nuts, enriched flour, green vegetables, etc. The vitamin is essential for normal cellular growth and function and best known for converting energy from protein, fat, and carbohydrates during metabolism and its antioxidant effects in oxidation-reduction reactions.
Breast cancer (malignant breast neoplasm) is a cancer that starts in the tissues of the breast either from the inner lining of milk ducts (Ductal carcinoma) or the lobules (Lobular carcinoma) that supply the ducts with milk. there is also rare cases that breast cancer starts in other areas of the breast. In 2010, over 250,000 new cases of breast cancer were expected to be diagnosed in women in the U.S. alone and the risk of getting invasive breast cancer during life time of a women is 1/8.

Epidemiological studies, focusing in the benefits of vitamin B2 in reduced risk  and treatment of breast cancer have produced an inconclusive results. Serum levels of riboflavin (RF) was found  significant decrease  and over-expressed of RF carrier protein  in women with breast cancer, administration of RF-targeted MMC-conjugate (mitomycin C (MMC)-conjugated N-(2-hydroxypropyl) methacrylamide (HPMA) [used as macromolecular carriers to enhance therapeutic efficacy and limit side effects of anti-cancer chemotherapeutic agents] enabled an increase in MMC uptake and nuclear localization in cell cyle to induce cytotoxic activity in in both MCF-7 and SKBR-3 cells(1).  In a follow-up of 20,756 women from the Melbourne Collaborative Cohort Study, including modification by age, hormone receptor status and alcohol consumption showed a insignificant evidence for an inverse association between breast cancer risk and riboflavin intake(2). Other in breast cancer risk among Japanese women, found no correlation of vitamin B2 intake and no overall association with breast cancer risk(3)(3a). Unfortunately, a 5-year survival rate study for in ER-/PR- breast cancers among Korean women, showed that a high intake of vitamin B2 and folate statistically elevated the HR of breast cancer progression compared to a low intake(4).

In postmenopausal women with breast cancer,  Tamoxifen (TAM) co administration with Coenzyme Q(10), Riboflavin and Niacin (CoRN)  exhibited a favorable impact on various blood chemistry profiles in reducing side effect of Tamoxifen causes of oxidative stress with various biochemical derangements(5), through increased the antioxidants status, while decreasing lipid and lipid peroxides(6)(7). In an 84 breast cancer patients randomized to receive a daily supplement of CoQ(10) 100 mg, riboflavin 10 mg and niacin 50 mg (CoRN), one dosage per day along with tamoxifen (TAM) 10 mg twice a day, supplementing CoRN  decreased the levels of pro-angiogenic factors and increase the levels of anti-angiogenic factors, enhanced the efficacy of the treatment and might even offered protection from cancer metastases and recurrence(8)(9)(10). Energy-modulating vitamins, riboflavin (45 mg/kg body weight per d), niacin (100 mg/kg body weight per d) and coenzyme Q10 (40 mg/kg body weight per d) for 28 days in the experiment against mammary carcinoma induced by the oral administration of 7,12-dimethylbenz[a]anthracene (25 mg/kg body weight), showed an decreasing of the Krebs cycle and oxidative phosphorylation enzymes and may be considered as a major therapeutic value in breast cancer(11).
Taking altogether, vitamin B2 when uses conjunction with other energy vitamin and in co administration with Tamixofen showed to enhance the efficacy of the chemo-agent by exerting its antioxidant effects. In fact, risk of breast cancer are associated to nutrient deficiency of vitamin B-12, thiamin, folacin, iron, and riboflavin(12). Over doses for a prolong period of time may cause symptoms of skin rashes, hypersensitivity, high blood pressure etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.
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References
(1) Riboflavin-targeted polymer conjugates for breast tumor delivery by Bareford LM, Avaritt BR, Ghandehari H, Nan A, Swaan PW.(PubMed)
(2) Dietary intake of B vitamins and methionine and breast cancer risk by Bassett JK, Baglietto L, Hodge AM, Severi G, Hopper JL, English DR, Giles GG.(PubMed)
(3) Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case-control study in Japan by Ma E, Iwasaki M, Kobayashi M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S.(PubMed)
(3a) Folate, vitamin B12 and postmenopausal breast cancer in a prospective study of French women by Lajous M, Romieu I, Sabia S, Boutron-Ruault MC, Clavel-Chapelon F.(PubMed)
(4) Prognosis of breast cancer is associated with one-carbon metabolism related nutrients among Korean women by Lee Y, Lee SA, Choi JY, Song M, Sung H, Jeon S, Park SK, Yoo KY, Noh DY, Ahn SH, Kang D.(PubMed)
(5) Effect of Coenzyme Q(10), Riboflavin and Niacin on Tamoxifen treated postmenopausal breast cancer women with special reference to blood chemistry profiles by Yuvaraj S, Premkumar VG, Shanthi P, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)
(6) Augmented antioxidant status in Tamoxifen treated postmenopausal women with breast cancer on co-administration with Coenzyme Q10, Niacin and Riboflavin by Yuvaraj S, Premkumar VG, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)
(7) Augmented efficacy of tamoxifen in rat breast tumorigenesis when gavaged along with riboflavin, niacin, and CoQ10: effects on lipid peroxidation and antioxidants in mitochondria by Perumal SS, Shanthi P, Sachdanandam P.(PubMed)
(8) Anti-angiogenic potential of CoenzymeQ10, riboflavin and niacin in breast cancer patients undergoing tamoxifen therapy by Premkumar VG, Yuvaraj S, Sathish S, Shanthi P, Sachdanandam P.(PubMed)
(9) Serum cytokine levels of interleukin-1beta, -6, -8, tumour necrosis factor-alpha and vascular endothelial growth factor in breast cancer patients treated with tamoxifen and supplemented with co-enzyme Q(10), riboflavin and niacin by Premkumar VG, Yuvaraj S, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubMed)
(10) Effect of coenzyme Q10, riboflavin and niacin on serum CEA and CA 15-3 levels in breast cancer patients undergoing tamoxifen therapy by Premkumar VG, Yuvaraj S, Vijayasarathy K, Gangadaran SG, Sachdanandam P.(PubNMed)
(11) Energy-modulating vitamins--a new combinatorial therapy prevents cancer cachexia in rat mammary carcinoma by Perumal SS, Shanthi P, Sachdanandam P.(PubMed)
(12) Taste perception and breast cancer: evidence of a role for diet by Ames HG, Gee MI, Hawrysh ZJ.(PubMed)

Breast cancer in Vitamin K's Point of View

 By Kyle J. Norton(Draft article)

Vitamin K(K1, phylloquinone; K2, menaquinones), is a fat soluble vitamin, found abundantly in leafy green vegetables, broccoli, and Brussels sprouts, etc. It is best known for promotion of coagulation and bone health.
Epidemiological studies focused in the synthetic version of vitamin K(Vk3) in reduced risk and treatment of breast cancer have proven successful in certain extents. In comparison of the anti cancer effects of Vitamin K (VK) congeners, vitamin K3(Menadione ), is a synthetic analogue with the same properties as provitaminis found to be most potent in treating varies types of cancer, including breast cancer(1) In comparison the inhibition effects of vitamin K, K3 and warfarin in human cancer cell lines, the combination of 3 Completely inhibited of L1210 growth in flask culture at concentrations of 200 micrograms/ml of warfarin, 75 micrograms/ml of vitamin K1, and 4 micrograms/ml of vitamin K3. The combination K3 and warfarin enhanced cytotoxicity at doses depending manner. Vitamin K3 alone was also cytotoxic in a concentration of 1 micrograms/ml, including breast cancers(1a). Synthesized VK2 derivatives (MQ-1, MQ-2 and MQ-3, also in the comparison of the antitumor activities of vitamin K1, K2, and K3 against a panel of human cancer cell lines, Vitamin K3 showed inhibition of various cancers and radioresistant cancers including breast cancer cell lines (BC-M1)( in doeses of 26, 15, 25, and 33 microM: VK1 ranged from 6 to 9 mM, and VK2 ranged from 1 to 2 mM in ID50 values(1b).

In breast cancer, vitamin K3 analogue plumbagin exerted its inhibitor effect of osteoclastogenesis induced by tumor cells and breast cancer-induced osteolytic metastasis through suppression of RANKL signaling to alter metastasis(2). In breast cancer cell line MCF-7, VK(3) exhibited cytotoxicity through DNA fragmentation (separation or breaking of DNA strands into pieces) and mitochondrial dysfunction(3).
In MCF-7, estrogen receptor-positive breast cancer cells, vitamin K3 (menadione) inhibited the transcriptional activity of 17beta-estradiol in a reporter gene assay(4). CR108, a novel vitamin K3 derivative, (S)-2-(2-hydroxy-3-methylbutylthio)naphthalene-1,4-dione, exhibited apoptosis in both the non-HER-2-overexpressed MCF-7 and HER-2-overexpressed BT-474 breast cancer cells, through induced the loss of mitochondrial membrane potential, leading to cytochrome c released from mitochondria to cytosol and and cleaved PARP(activate CNS immune responses) proteins(5). Menadione, also known as VK3, its reduction-oxidation, generated by ascorbate-driven menadione redox cycling inhibited MCF7 breast cancer cells, through glycolysis(metabolic pathway for generation of energy) inhibition, loss of calcium homeostasis(maintains adequate calcium levels), DNA damage and changes in mitogen activated protein kinases (MAPK)(regulate proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis ) activities(6). Also, in MCF 7 breast cancer cells, Fluorinated Cpd 5, an arylating K-vitamin derivative, showed growth inhibition probably via conjugation of cellular thiols, by suppressing the activity of thiol containing cellular protein tyrosine phosphatase (PTP) enzyme(play critical roles in fundamental biological processes), with consequent induction of various tyrosine phosphoproteins(involved in a number of metabolic and signalling pathways) in promoting mutation cell proliferation(7).

Vitamin K although was found effectively in decreased risk and treatment for breast cancers by exhibition of it effects in cytotoxicity, apoptosis and anti proliferation through DNA fragmentation, mitochondrial dysfunction, cell death pathway. Overdoses can induced symptoms of Skin rash,  Diarrhea, Nausea, Vomiting, Anemia, etc. Please make sure you follow the of the Institute of Medicine of the National Academies.
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References
(1) Comparison of antitumor activity of vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB) cell viability assays by Wu FY, Liao WC, Chang HM.(PubMed)
(1a) Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation. by Chlebowski RT, Dietrich M, Akman S, Block JB.(PubMed)
(1b) Vitamin K2-derived compounds induce growth inhibition in radioresistant cancer cells by Amalia H, Sasaki R, Suzuki Y, Demizu Y, Bito T, Nishimura H, Okamoto Y, Yoshida K, Miyawaki D, Kawabe T, Mizushina Y, Sugimura K(PubMed).
(2) Plumbagin inhibits osteoclastogenesis and reduces human breast cancer-induced osteolytic bone metastasis in mice through suppression of RANKL signaling by Sung B, Oyajobi B, Aggarwal BB.(PubMed)
(3) The potential of vitamin K3 as an anticancer agent against breast cancer that acts via the mitochondria-related apoptotic pathway by Akiyoshi T, Matzno S, Sakai M, Okamura N, Matsuyama K.(PubMed)
(4) Anti-estrogenic activity of fifty chemicals evaluated by in vitro assays by Jung J, Ishida K, Nishihara T.(PubMed)
(5) CR108, a novel vitamin K3 derivative induces apoptosis and breast tumor inhibition by reactive oxygen species and mitochondrial dysfunction by Yang CR, Liao WS, Wu YH, Murugan K, Chen C, Chao JI.(PubMed)
(6) Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells by Beck R, Verrax J, Dejeans N, Taper H, Calderon PB.(PubMed)
(7) Growth inhibition and protein tyrosine phosphorylation in MCF 7 breast cancer cells by a novel K vitamin by Kar S, Carr BI.(PubMed)