Thursday, February 20, 2014

Prostate cancer in Vitamin B6's Points of View

 Kyle J.Norton(Draft Article)

Vitamin B6, also known as pyridoxine, is a water soluble vitamin found abundantly in green peas, yams, broccoli, asparagus and turnip greens,Peanuts, sunflower seeds, cashews and hazelnuts, meat, fish etc., with functions of amino acid, carbohydrate  metabolism, brain health, and liver detoxification, etc.

Prostate cancer, a second leading cause of cancer death in men is defined as a condition in which the cells of prostate has become cancerous, causing abnormal cell growth with possibility of spreading to the distant parts of the body.
.
Epidemiological studies, focusing pyridoxine in reduced risk and treatment of prostate cancer have been inconclusive. Study of the  link between intake of Folate, Methionine, and Vitamins B-12, B-6 and Prostate Cancer Risk in American Veterans, showed no evidence for associations between B vitamins (folate, B12, and B6) and PC risk(1) and In the one-carbon metabolism and prostate cancer risk, researcher found no convincing evidence for a protective role of one-carbon metabolism against prostate cancer(2).  Dietary methyl groups(methionine, one-carbon units and choline (or the choline metabolite betaine) showed a a protective effect on the development of higher grades of prostate cancer in the "Hi-myc" mouse model of prostate cancer(3). Other suggestion indicated that high vitamin B-6 intake may improve prostate cancer survival among men with a diagnosis of localized-stage disease(4). A case-control study of diet and prostate cancer, included 328 men diagnosed with prostate cancer before the age of 75 years and 328 age-matched population controls, vitamin B6 was associated to reduced risk of prostate cancer(5)

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References
(1) Associations between Intake of Folate, Methionine, and Vitamins B-12, B-6 and Prostate Cancer Risk in American Veterans by Vidal AC, Grant DJ, Williams CD, Masko E, Allott EH, Shuler K, McPhail M, Gaines A, Calloway E, Gerber L, Chi JT, Freedland SJ, Hoyo C.(PubMed)
(2) Dietary factors of one-carbon metabolism and prostate cancer risk by Weinstein SJ, Stolzenberg-Solomon R, Pietinen P, Taylor PR, Virtamo J, Albanes D.(PubMed)
(3) Progression of prostate carcinogenesis and dietary methyl donors: temporal dependence by Shabbeer S, Williams SA, Simons BW, Herman JG, Carducci MA.(PubMed)
(4) One-carbon metabolism-related nutrients and prostate cancer survival by Kasperzyk JL, Fall K, Mucci LA, Håkansson N, Wolk A, Johansson JE, Andersson SO, Andrén O.(PubMed)
(50) A case-control study of diet and prostate cancer by Key TJ, Silcocks PB, Davey GK, Appleby PN, Bishop DT(PubMed)

Wednesday, February 19, 2014

Prostate cancer in Vitamin B2's Points of View


Kyle J.Norton(Draft Article)

Vitamin B2 also known as 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.

Prostate cancer is defined as a condition in which the cells of prostate has become cancerous, causing abnormal cell growth with possibility of spreading to the distant parts of the body. Most prostate cancers are slow growing and enlarged prostate and prostate cancer may be detected during physical (rectum) exams.
Over expression of riboflavin carrier protein (RCP) in prostate cancer patient may ve used as a marker in -targeted diagnosis and for the assessment of vascular metabolism in tumors(6). In localized both androgen-dependent and independent prostate cancer cell lines, Antibodies to chicken RCP inhibited incorporation of tritiated thymidine into DNA and prevented riboflavin uptake in PC3 prostate cancer cells(7). Other suggestion of elevated plasma concentrations of choline and vitamin B2 may be associated with an increased risk of prostate cancer(8).

Epidmeiological studies, linking vitamin B2 in reduced risk of prostate cancer have produced inconsistent results. In prostae cancer cell line cancer (LnCap), vitamin B2 intakes were not associated with prostate cancer survival(1) and dietary supplements, including vitamn B2 effective treatments for PC patients is not supported by sound clinical evidence(2).  Luckily, in the study of Cancer Research and Product Development Laboratory, Immunal Ltd, active mixture AM: L-arginine, L-histidine, L-methionine, L-phenylalanine, L-tyrosine, L-tryptophan, L-ascorbate, D-biotin, pyridoxine, riboflavin, adenine, L(-)malate), induced apoptosis through the mitochondrial pathway and G1 arrest in PC-3 cells and in PC-3 xenografts(3). Also in the interaction of interaction between β-cyclodextrin (βCD) or hydroxypropyl-β-cyclodextrin (HPβCD) and riboflavin (RF) indicated that both RF-βCD and RF-HPβCD complexes were cytotoxic to PC3 prostate cancer cells(4). Other suggestion showed a weak associations between prostate cancer incidence and dietary intake of riboflavin and between riboflavin intake and prostate cancer mortality(5). But in the study of the role of diet in prostate cancer, researchers suggested that intake of  linoleic acid and riboflavin (in subjects 50 years and over) could be protective when compared with control subjects(10)and the study of the effects of irradiated riboflavin on androgen-independent human, by Universidade Estadual de Campinas, showed  that riboflavin photoproducts are cytotoxic to these cells in a FasL-Fas-dependent manner, through inhibited matrix-degrading proteases(invloved both the process of ECM remodeling and angiogenesis, and in a potential causal relationship between these processe) caused downregulation of VEGF(vascular endothelial growth factor ) and upregulation of TIMP1(inhibitor of metalloproteinases)(9).

Taking altogether, riboflavin carrier protein (RCP) may be used as a marker in targeted diagnosis of prostate cancer and  Vitamin B2 may be  considered as a vital component of any treatment plan instead of sole means of cancer prevention and treatment in Prostate cancer patients. Over doses for a prolong period 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) One-carbon metabolism-related nutrients and prostate cancer survival by Kasperzyk JL, Fall K, Mucci LA, Håkansson N, Wolk A, Johansson JE, Andersson SO, Andrén O(PubMed)
(2) Dietary supplements and prostate cancer: a systematic review of double-blind, placebo-controlled randomised clinical trials by Posadzki P, Lee MS, Onakpoya I, Lee HW, Ko BS, Ernst E.(PubMed)
(3) A mixture of amino acids and other small molecules present in the serum suppresses the growth of murine and human tumors in vivo by Kulcsár G, Gaál D, Kulcsár PI, Schulcz Á, Czömpöly T(PubMed)
(4) Non-inclusion complexes between riboflavin and cyclodextrins by de Jesus MB, Fraceto LF, Martini MF, Pickholz M, Ferreira CV, de Paula E(PubMed)
(5) Dietary intake of B vitamins and methionine and prostate cancer incidence and mortality by Bassett JK, Severi G, Hodge AM, Baglietto L, Hopper JL, English DR, Giles GG.(PubMed)
(6) Riboflavin carrier protein-targeted fluorescent USPIO for the assessment of vascular metabolism in tumors by Jayapaul J, Arns S, Lederle W, Lammers T, Comba P, Gätjens J, Kiessling F(PubMed)
(7) Biochemical characterization of riboflavin carrier protein (RCP) in prostate cancer by Johnson T, Ouhtit A, Gaur R, Fernando A, Schwarzenberger P, Su J, Ismail MF, El-Sayyad HI, Karande A, Elmageed ZA, Rao P, Raj M(PubMed)
(8) One-carbon metabolism and prostate cancer risk: prospective investigation of seven circulating B vitamins and metabolites by Johansson M, Van Guelpen B, Vollset SE, Hultdin J, Bergh A, Key T, Midttun O, Hallmans G, Ueland PM, Stattin P(PubMed)
(9) A possible anti-proliferative and anti-metastatic effect of irradiated riboflavin in solid tumours by de Souza Queiroz KC, Zambuzzi WF, Santos de Souza AC, da Silva RA, Machado D, Justo GZ, Carvalho HF, Peppelenbosch MP, Ferreira C(PubMed)
(10) The role of diet in prostate cancer by Kaul L, Heshmat MY, Kovi J, Jackson MA, Jackson AG, Jones GW, Edson M, Enterline JP, Worrell RG, Perry SL(PubMed)

Tuesday, February 18, 2014

Prostate cancer in Vitamin D's Points of View

Kyle J. Norton(Draft Article)

Vitamin D is a fat-soluble secosteroids found in small amount in few foods, including salmon, mackerel, sardines and tuna. The vitamin plays an important role in modulation of cellular proliferation, apoptosis induction, tumor growth suppression and promotion in absorption of minerals, including calcium, iron, magnesium, phosphate and zinc.
The widespread of prostate cancer, once considered as a disease of aging male, now have become major concerns of governments and scientific community in South East Asian with tendency to spread to younger age population. Suggestions emerged of over consuming bad fats in any time in history accompanied with unhealthy diet and life style may be the possible causes of the disease, linking to the economic prosperity over 2 decades. Herbal medicine for diseases' management have been prescribed in folk medicine over thousands of year as one of best medicine of nature in preventing and treating diseases, including prostate cancer.

Genetic mutation
Genetic mutation of Vitamin D-deactivating enzyme CYP24A1may be associated to increased risk of prostate cancer. In a Korean cohort suggested that five CYP24A1 sequence variants (rs2248461,  rs2248359, rs602299, rs2585428, rs4809959 had a significant association with prostate cancer risk(1);
vitamin D receptor (VDR) gene (two VDR sequence variants (rs2408876 and rs2239182), may play an important role in the onset and progression of prostate cancer(2). Others study of vitamin D pathway genes, VDR, CYP27B1, and CYP24A1, in prostate cancer showed an conflict result of that genotypes of CYP27B1 and CYP24A1 were not associated with prostate cancer risk, but polymorphisms in the VDR gene may be(3)(4)(5). In common genetic variation of the calcium-sensing receptor(CaSR), the Harvard School of Public Health showed that CaSR may be involved in PCa progression(5a)

Vitamin D plasma
Suggestions of plasma used in measurement of risk of prostate have been controversial with many inconsistent results, epidemiological. The population-based cohort study of 1476 prostate cancer patients to assess disease recurrence/progression and prostate cancer-specific mortality (PCSM) risks associated with serum levels of 25(OH) vitamin D [25(OH)D], showed no evidence of serum vitamin D levels measured after diagnosis associated to prostate cancer prognosis(6) and  according to the Oregon Health & Science University prospective cohort of older men also found no association between serum 25-OH vitamin D levels and subsequent risk of prostate cancer.(6a). But according to the Harvard Medical School, suboptimal vitamin D status (especially during the winter/spring season), and both 25(OH)D and 1,25(OH)2D may play an important role in preventing prostate cancer progression(7) and  higher prediagnostic plasma 25(OH)D might be associated with improved prostate cancer prognosis(8).
In the variation of  above, some researchers suggested that  plasma 25(OH)D levels associated to common variation among several vitamin D-related genes((CYP27A1, CYP2R1, CYP27B1, GC, CYP24A1, RXRA, and VDR) and calcium-sensing receptor (CaSR)were associated with lethal prostate cancer risk(9)(10)(11). A report of survival in veterans with prostate cancer indicated a veterans who are initially vitamin D deficient and both initial and follow-up vitamin D deficiency are associated with decreased likelihood of survival after prostate cancer diagnosis(12). Other suggestions, linking vitamin D in reduced risk of prostate cancer and  prostate cancer-related health disparities in African-American men were greatly involved at least in part the result of widespread hypovitaminosis D within the African-American population.(15).


The efficacy
Vitamin D most active form, 1,25D(3) in an experiment of a stable prostate cancer cell line PC3 with CYP24A1 promoter inhibited gene expression of CYP24A1 through enhancement and regulation of  a protein kinase CK2 selective inhibitor(13); exhibited tumor suppressive miRNAs in patient prostate tissue, thus decreased proliferation in primary cells and cancer cells and suppressed migration and clonal growth of prostate cancer cell in a miRNA-dependent manner(14). A report from the Medical University of South Carolina, showed that vitamin D(3) supplementation at 4000 IU/d for 1 year, in patients with low-risk prostate cancer under active surveillance may benefit from vitamin D(3) supplementation(16) and eliminated any significant differences in circulating concentrations of 25(OH)D between African American and white men(17). Unfortunately, the University of Oslo study within Norwegian health studies indicated a increased risk of prostate cancer related to a high 25(OH)D concentration only during the summer and autumn due to vitamin D itself or to other factors associated with sun exposure(18). The discrepancy between the results of studies of solar exposure and studies of serum 25-OHD may be related to methodological differences and to uncertainties regarding the critical period for vitamin D exposure(19). The same author also suggested that low levels of UV radiation/vitamin D are indeed associated with an increased risk of prostate cancer in individual men(20).

Taking altogether, without going into reviews, although it is controversial, vitamin D may be effectively and selectively in reduced risk and treatment for prostate cancer in hypovitamin D deficient men and without exposure to UV sunlight and the disagreement of amount of vitamin D intake and plasma level in reduced risk and treatment of prostate cancer may still need further studies. Over doses of vitamin D supplement may cause excessive calcium absorption, calcification, Urinary stones etc. please make sure to follow the guideline of the Institute of Medicine of the National Academies.
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References
(1) Genetic variants in the CYP24A1 gene are associated with prostate cancer risk and aggressiveness in a Korean study population. by Oh JJ1, Byun SS2, Lee SE2, Hong SK2, Jeong CW2, Choi WS3, Kim D4, Kim HJ5, Myung SC6(PubMed)
(2) Genetic variations in VDR associated with prostate cancer risk and progression in a Korean population by Oh JJ, Byun SS, Lee SE, Hong SK, Jeong CW, Kim D, Kim HJ, Myung SC(PubMed)
(3) Comprehensive association analysis of the vitamin D pathway genes, VDR, CYP27B1, and CYP24A1, in prostate cancer by Holick CN, Stanford JL, Kwon EM, Ostrander EA, Nejentsev S, Peters U.(PubMed)
(3) Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review by Chen L, Davey Smith G, Evans DM, Cox A, Lawlor DA, Donovan J, Yuan W, Day IN, Martin RM, Lane A, Rodriguez S, Davis M, Zuccolo L, Collin SM, Hamdy F, Neal D, Lewis SJ(PubMed)
(5) Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk by Raimondi S, Johansson H, Maisonneuve P, Gandini S(PubMed)
(5a) Common genetic variation of the calcium-sensing receptor and lethal prostate cancer risk by Shui IM, Mucci LA, Wilson KM, Kraft P, Penney KL, Stampfer MJ, Giovannucci E(PubMed)

(6) Circulating levels of 25-hydroxyvitamin D and prostate cancer prognosis by Holt SK, Kolb S, Fu R, Horst R, Feng Z, Stanford JL.(PubMed)
(7) A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms, and prostate cancer by Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, Giovannucci EL, Ma J(PubMed)
(8) Prediagnostic plasma vitamin D metabolites and mortality among patients with prostate cancer by Fang F, Kasperzyk JL, Shui I, Hendrickson W, Hollis BW, Fall K, Ma J, Gaziano JM, Stampfer MJ, Mucci LA, Giovannucci E(PubMed)
(9) Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study by Shui IM, Mucci LA, Kraft P, Tamimi RM, Lindstrom S, Penney KL, Nimptsch K, Hollis BW, Dupre N, Platz EA, Stampfer MJ, Giovannucci E(PubMed)
(10) Common genetic variation of the calcium-sensing receptor and lethal prostate cancer risk by Shui IM, Mucci LA, Wilson KM, Kraft P, Penney KL, Stampfer MJ, Giovannucci E(PubMed)
(11) Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk by Ahn J, Albanes D, Berndt SI, Peters U, Chatterjee N, Freedman ND, Abnet CC, Huang WY, Kibel AS, Crawford ED, Weinstein SJ, Chanock SJ, Schatzkin A, Hayes RB; Prostate, Lung, Colorectal and Ovarian Trial Project Team(PubMed)
(12)Vitamin d and prostate cancer survival in veterans by Der T1, Bailey BA2, Youssef D1, Manning T3, Grant WB4, Peiris AN(PubMed)
(13) Inhibition of protein kinase CK2 reduces Cyp24a1 expression and enhances 1,25-dihydroxyvitamin D(3) antitumor activity in human prostate cancer cells by Luo W, Yu WD, Ma Y, Chernov M, Trump DL, Johnson CS.(PubMed)
(14) Tumor suppressor microRNAs, miR-100 and -125b, are regulated by 1,25-dihydroxyvitamin D in primary prostate cells and in patient tissue by Giangreco AA, Vaishnav A, Wagner D, Finelli A, Fleshner N, Van der Kwast T, Vieth R, Nonn L.(PubMed)
(15) Vitamin D3 supplementation, low-risk prostate cancer, and health disparities by Hollis BW, Marshall DT, Savage SJ, Garrett-Mayer E, Kindy MS, Gattoni-Celli S(PubMed)
(16) Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance by Marshall DT, Savage SJ, Garrett-Mayer E, Keane TE, Hollis BW, Horst RL, Ambrose LH, Kindy MS, Gattoni-Celli S.(PubMed)
(17) Vitamin D3 supplementation (4000 IU/d for 1 y) eliminates differences in circulating 25-hydroxyvitamin D between African American and white men by Garrett-Mayer E, Wagner CL, Hollis BW, Kindy MS, Gattoni-Celli S.(PubMed)
(18) Vitamin D, season, and risk of prostate cancer: a nested case-control study within Norwegian health studies by Meyer HE, Robsahm TE, Bjørge T, Brustad M, Blomhoff R.(PubMed)
(19) Vitamin D, sunlight, and the epidemiology of prostate cancer by Schwartz GG.(PubMed)
(20) Vitamin D and the epidemiology of prostate cancer by Schwartz GG.(PubMed)


















Monday, February 17, 2014

Prostate cancer in Vitamin C's Points of View

 Kyle J. Norton(Draft Article)

The widespread of prostate cancer, once considered a disease of aging male, now have become major concerns of governments and scientific community in South East Asian with tendency to effect even younger age population.

Vitamin C, also known as L-ascorbic acid, is a water-soluble vitamin, found in fresh fruits, berries and green vegetables. It is best known for its free radical scavengers activity and regenerating oxidized vitamin E for immune support.

Epidmeiological studies, linking vitamin C in reduced risk and treatment of prostate cancer have produced inconsistent results.
In reviewed studies examined the relationship between prostate cancer and antioxidants indicated that there is no strong evidence for a beneficial effect of selenium, vitamin C, or beta-carotene, in reduced risk of prostate cancer and effect of dietary antioxidants on prostate cancer remains undefined and inconclusive(1). Supplemental vitamin C, in 1338 cases of prostate cancer among 29 361 men during up to 8 years of follow-up, also showed no strong support for high-dose antioxidant supplementation for the prevention of prostate cancer(2).
On Androgen-independent (DU145) and androgen-dependent (LNCaP) human prostate cancer cell lines, vitamin C inhibited prostate cancer cell proliferation through production of unidentified free radical(s) generation of hydrogen peroxide(3) and PC-3 through reactive oxygen specie(4) or through increased with temperature in cancer cells(5). Combination of Fe3O4@C nanoparticles (NPs) and Ascorbic acid (AA) enhanced cytotoxicity of PC-3 cells, through created hydroxyl radicals via an oxidative stress process(6). On intravenous (i.v.) vitamin C or ascorbic acid (ascorbate, vitamin C treatment depleted Adenosine triphosphate(ATP)(transports chemical energy within cells for metabolism) and induced autophagy in sensitive prostate cancer cells{(LaPC4)and  in five of the six tested prostate cancer cell lines}(7).
In a study of mixture of nutrients (NM) containing lysine, proline, ascorbic acid and green tea extract, showed that NM inhibited prostate cancer cell line PC-3 and DU-145 through suppression of the secretion of u-PA subunit 1(correlated with matrix proteolysis, cell adhesion, motility, and invasion)(8). Combination of Monensin and vitamin C study showed an enhancement of vitamin C in exhibition of the effect of  Monensin in induced apoptosis through increased generation of intracellular reactive oxygen species and by induction of a transcriptional profile characteristic of an oxidative stress response(9). in
redox-active form of vitamin C, ascorbate induced apoptosis through induction of cell cycle arrest(10).

Taking altogether, without going through the reviews, vitamin C may be effective in reduced risk and treatment of prostate cancer through generation of reactive oxygen species(ROS), or cell cycle arrest when used alone or combination with other chemo-agents or phytochmecials. Daily ingestion of high-dose vitamin C may be considered safe, but in rare incidence, overdoses in a prolonged period of time, may cause intra-renal oxalate crystal deposition, a fatal nephrotoxicity(11)(22).

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References
(1) Dietary antioxidants and prostate cancer: a review by Vance TM, Su J, Fontham ET, Koo SI, Chun OK(PubMed)
(2) 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)


(3) Effect of vitamin C on prostate cancer cells in vitro: effect on cell number, viability, and DNA synthesis by Maramag C, Menon M, Balaji KC, Reddy PG, Laxmanan S(PubMed)
(4) Effect of vitamin C on androgen independent prostate cancer cells (PC3 and Mat-Ly-Lu) in vitro: involvement of reactive oxygen species-effect on cell number, viability and DNA synthesis by Menon M, Maramag C, Malhotra RK, Seethalakshmi L(PubMed)
(5) Peroxidase-like activity of Fe3O4@carbon nanoparticles enhances ascorbic acid-induced oxidative stress and selective damage to PC-3 prostate cancer cells by An Q, Sun C, Li D, Xu K, Guo J, Wang C.(PubMed)
(6) Effect of ascorbic acid on reactive oxygen species production in chemotherapy and hyperthermia in prostate cancer cells by Fukumura H, Sato M, Kezuka K, Sato I, Feng X, Okumura S, Fujita T, Yokoyama U, Eguchi H, Ishikawa Y, Saito T(PubMed)
(7) Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy by Chen P, Yu J, Chalmers B, Drisko J, Yang J, Li B, Chen Q(PubMed)
(8) Down-regulation of urokinase plasminogen activator and matrix metalloproteinases and up-regulation of their inhibitors by a novel nutrient mixture in human prostate cancer cell lines PC-3 and DU-145 by Roomi MW, Kalinovsky T, Rath M, Niedzwiecki A(PubMed)
(9) Monensin is a potent inducer of oxidative stress and inhibitor of androgen signaling leading to apoptosis in prostate cancer cells by Ketola K, Vainio P, Fey V, Kallioniemi O, Iljin K(PubMed)
(10) Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs by Frömberg A, Gutsch D, Schulze D, Vollbracht C, Weiss G, Czubayko F, Aigner A(PubMed)
(11) Fatal vitamin C-associated acute renal failure by McHugh GJ, Graber ML, Freebairn RC.(PubMed)
(12) Ascorbic acid overdosing: a risk factor for calcium oxalate nephrolithiasis by Urivetzky M, Kessaris D, Smith AD.(PubMed)








Saturday, February 15, 2014

Breast cancer in folate's Point of view

 By Kyle J. Norton(Draft article)

Folate, also known as folic acid, vitamin B9, is a water soluble vitamin, found abundantly in leafy vegetables, citrus fruits, beans, whole grain, etc. The vitamin plays an important role in synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions, production of red blood cells for anemia prevention.
Scientific studies, linking folate in reduced risk of breast cancer have produced inconsistent results. It may be due to associated vary by race, menopausal status or ER status(1). In comparison of the dietary intakes of folate, B-vitamins (B2, B6, B12) and methionine, showed that high intake of folate is marginally associated with a reduced lower risk for ER- breast cancer(1a), among Hispanic and non-Hispanic white women(2), but  among Brazilian women, dietary intake of folate,  had no overall association with breast cancer risk and high folate intake increased risk of breast cancer in premenopausal women with the MTR 2756GG genotype(women carry this gene have a subtly reduced risk of breast cancer(3))(4). In breast cancer risk defined by oestrogen receptor (ER) and progesterone receptor (PR) status, dietary folate intake showed an significant inverse association of breast cancer risk  in all subtypes of ER and PR status(5).
In Japanese women with genotypes of MTHFR or MTR, dietary intake of folate and related B vitamins have no overall association with breast cancer risk in Japanese women(6).
Unfortunately. in rat model study, folate supplementation was found to be associated with significantly higher weight and volume of all mammary tumors and might enhance the progression of established mammary tumors(7). Also in the study of at weaning, female pups, maternal folic acid supplementation also significantly accelerated the rate of mammary adenocarcinoma appearance and significantly decreased DNA methyltransferase (protect host DNA against degradation by restriction enzymes) activity in nonneoplastic(not tumors) mammary glands of the offspring(8). In the finding an anti breast caner conjugat used conjuction with Doxorubicin (Dox) which used for breast cancer treatment but causes serious side effects including cardiotoxicity, conjugation of  Dox-conjugated hairpin (DCH) with folic acid (FA) is found to be effective in increased internalization into breast cancer cells for safer and more effective chemotherapy with Dox(9). In MCF-7 and MDA-MB-231 breast cancer cells, hydrogel, based on ellagic acid and glycine containing folate acid significantly inhibit cell viability(10). In nude mice carrying xenograft MCF-7 tumours,  folate inTMX(Tamoxifen)-loaded folate-targeted systems anticancer action of TMX(11). Lipotropes are methyl group-containing essential nutrients (methionine, choline, folate and vitamin B12) in the experiment in MCF-7 cells, showed to significantly reduced cell growth and increased apoptosis, through upregulation of caspase-3(mechanisms of apoptosis) and P53(tumor antigen) enzyme activities(12). Also in the evaluation of MTHFR C677T-A1298C polymorphisms in patients with breast cancer, showed that at dose of 120 nmol/L FA could enhance apoptosis in cases with women who carry MTHFR C677T-A1298C genotype(13).

Taking together, folate used conjunction with other chem-drugs have shown effectively in enhancing the function the medicine in prevention and treatment of breast cancer cell lines with reduced side effects. Overdoses of folate may cause stomach problems, sleep problems, skin reactions, seizures, etc., please
 make sure you follow the guideline of the Institute of Medicine of the National Academies.
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References
(1) Associations of dietary folate, Vitamins B6 and B12 and methionine intake with risk of breast cancer among African American and European American women by Gong Z, Ambrosone CB, McCann SE, Zirpoli G, Chandran U, Hong CC, Bovbjerg DH, Jandorf L, Ciupak G, Pawlish K, Lu Q, Hwang H, Khoury T, Wiam B, Bandera EV.(PubMed)

(1a) Dietary intake of folate, B-vitamins and methionine and breast cancer risk among Hispanic and non-Hispanic white women by Yang D, Baumgartner RN, Slattery ML, Wang C, Giuliano AR, Murtaugh MA, Risendal BC, Byers T, Baumgartner KB.(PubMed)
(2) 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)
(3) Cancer: New Insights for the Healthcare Professional: 2012 Edition
(4) 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)
(5) 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)
(6) 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)
(7) Folic Acid supplementation promotes mammary tumor progression in a rat model. by Deghan Manshadi S1, Ishiguro L1, Sohn KJ2, Medline A3, Renlund R4, Croxford R5, Kim Y1(PubMed)
(8) Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring by Ly A, Lee H, Chen J, Sie KK, Renlund R, Medline A, Sohn KJ, Croxford R, Thompson LU, Kim YI.(PubMed)
(9)Site-Specific DNA-Doxorubicin Conjugates Display Enhanced Cytotoxicity to Breast Cancer Cells by Stuart CH, Horita DA, Thomas MJ, Salsbury FR Jr, Lively MO, Gmeiner WH.(PubMed)
(10) Anticancer activity of a hydrogel containing folic acid towards MCF-7 and MDA-MB-231 cells by Trombino S, Ferrarelli T, Pellegrino M, Ricchio E, Mauro L, Andò S, Picci N, Cassano R.(PubMed)
(11) Targeting Tamoxifen to Breast Cancer Xenograft Tumours: Preclinical Efficacy of Folate-Attached Nanoparticles Based on Alginate-Cysteine/Disulphide-Bond-Reduced Albumin by Martínez A, Muñiz E, Teijón C, Iglesias I, Teijón JM, Blanco MD.(PubMed)
(12) Lipotropes enhance the anti-proliferative effect of chemotherapeutic drugs in MCF-7 human breast cancer cells by Cho K, Mabasa L, Walters MW, Park CS.(PubMed)
(13) Interactions between MTHFR C677T-A1298C variants and folic acid deficiency affect breast cancer risk in a Chinese population by Wu XY, Ni J, Xu WJ, Zhou T, Wang X.(PubMed)







Friday, February 14, 2014

Prostate cancer in Vitamin E's Points of View

The widespread of prostate cancer, once considered as a disease of aging male, now has become major concerns of governments and scientific community in South East Asian with tendency to effect even younger age population. Epidemiological studies, linking vitamin E in reduced risk of prostate cancer have produced conflict results. It may be due to age related, smoking habit, gene mutation, types of tocopherol, etc.

Prostate cancer is defined as a condition in which the cells of prostate has become cancerous, causing abnormal cell growth with possibility of spreading to the distant parts of the body. Most prostate cancers are slow growing and enlarged prostate and prostate cancer may be detected during physical (rectum) exams.

The conflict results
The Selenium and Vitamin E Cancer Prevention Trial (SELECT) showed an adverse effect of dietary supplement with vitamin E significantly increased the risk of prostate cancer among healthy men through illustration  per 1000 person-years.(1)or prevented the development of prostate cancer in the population of relatively healthy men(2). In the study of  combination used of vitamin C and E of total of 14,641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, also suggested that neither vitamin E nor C supplementation reduced the risk of prostate or total cancer(3). Positively, on prostate cancer (PCa), in N-methyl-N-nitrosourea (MNU)-induced epithelial dysplasia in the rat ventral prostate (VP), animals fed a control+γ-tocopherol (CT+γT)  significantly attenuated the adverse effects of MNU in the VP through the deceased epithelial dysplasia, along with the cell proliferation index, GST-pi and Cox-2 immunoexpression(3). Some researchers insisted that different forms of vitamin E exert different effects on prostate cancer, with alpha-tocopherol potentially increasing and gamma-tocopherol potentially decreasing risk of the disease(5).



The serum of tocopherol
In the study of the effects of Serum α-tocopherol and γ-tocopherol in prostate cancer patient showed  that  higher serum α-tocopherol was associated with significantly lower prostate cancer risk and by contrast, risk was non-significantly elevated among men with higher γ-tocopherol concentrations(12).
Some researchers suggested that higher prediagnostic serum concentrations of alpha-tocopherol, but not dietary vitamin E, was associated with lower risk of developing prostate cancer, particularly advanced prostate cancer(13). But in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, showed that risk of prostate cancer reduced with high serum tocopherols and  higher circulating concentrations of the major vitamin E fractions, alpha-tocopherol and gamma-tocopherol(14) and higher alpha-tocopherol (and not beta-carotene or retinol) status increases overall prostate cancer survival(15).



The benefits
Study of 8-wk-old male TRAMP mice were fed 0.1% γ-TmT or a control diet for 16 weeks, Nuclear factor-erythroid 2-related factor 2 (Nrf2), showed that γ-tocopherol-rich mixture of tocopherols (γ-TmT) inhibited CpG methylation (promoters of genes can lead to their silencing, a feature found in a number of human cancers ) in the Nrf2 promoter in the prostate of transgenic adenocarcinoma of the mouse prostate (TRAMP) and in TRAMP-C1 cells(6). In prostate cancer, combination use of NAG-1 and Vitamin E succinate (VES), showed the enhancement of VES in >3-fold increase in the half-life of NAG-1 mRNA through transcriptional/post-transcriptional mechanism in a p38 kinase-dependent manner(7). On prostate cancer in male smokers. long-term supplementation with alpha-tocopherol substantially reduced prostate cancer incidence and mortality(8). In the study of  the incidence of prostate cancer risk associations of alpha-tocopherol, gamma-tocopherol, and selenium, indicated that risk of prostate cancer declined, but not linearly, with increasing concentrations of alpha-tocopherol; gamma-tocopherol, men in the highest fifth of the distribution had a fivefold reduction in the risk of developing prostate cancer than men in the lowest fifth(9).
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of 29,133 Finnish male smokers aged 50-69 years, showed a decreased risk of prostate cancer with oral administration of daily α-tocopherol (50 mg) for a median of 6.1 years and lower prostate cancer mortality(10). Other suggestion of inhibitory prostate cancer activities of δ-T and γ-T (than α-T) may be as a result of  due trapping of reactive nitrogen species and their capacity to generate side-chain degradation products(11).



Taking altogether, most researchers agreed that intake of alpha-tocopherol  may be beneficiary in reduced risk and treatment of prostate cancer accompany of diet,  life style change(16)(17)(18). Over doses of vitamin E supplement can cause symptoms of blurred vision, weakness, dizziness, nausea, diarrhea, etc., please make sure you follow the guideline of the Institute of Medicine of the National Academies.

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References
(1) Vitamin E and the risk of prostate cancer: the Selenium and Vitamin E Cancer Prevention Trial (SELECT) by Klein EA, Thompson IM Jr, Tangen CM, Crowley JJ, Lucia MS, Goodman PJ, Minasian LM, Ford LG, Parnes HL, Gaziano JM, Karp DD, Lieber MM, Walther PJ, Klotz L, Parsons JK, Chin JL, Darke AK, Lippman SM, Goodman GE, Meyskens FL Jr, Baker LH(PubMed)
(2) Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT) byLippman SM, Klein EA, Goodman PJ, Lucia MS, Thompson IM, Ford LG, Parnes HL, Minasian LM, Gaziano JM, Hartline JA, Parsons JK, Bearden JD 3rd, Crawford ED, Goodman GE, Claudio J, Winquist E, Cook ED, Karp DD, Walther P, Lieber MM, Kristal AR, Darke AK, Arnold KB, Ganz PA, Santella RM, Albanes D, Taylor PR, Probstfield JL, Jagpal TJ, Crowley JJ, Meyskens FL Jr, Baker LH, Coltman CA Jr.(PubMed)
(3) Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial by Gaziano JM, Glynn RJ, Christen WG, Kurth T, Belanger C, MacFadyen J, Bubes V, Manson JE, Sesso HD, Buring JE(PubMed)
(4) Protective effect of γ-tocopherol-enriched diet on N-methyl-N-nitrosourea-induced epithelial dysplasia in rat ventral prostate by Sanches LD, Santos SA, Carvalho JR, Jeronimo GD, Favaro WJ, Reis MD, Felisbino SL, Justulin LA Jr(PubMed)
(5) Dietary antioxidants and prostate cancer: a review by Vance TM, Su J, Fontham ET, Koo SI, Chun OK.(PubMed)
(6) A γ-tocopherol-rich mixture of tocopherols maintains Nrf2 expression in prostate tumors of TRAMP mice via epigenetic inhibition of CpG methylation by Huang Y, Khor TO, Shu L, Saw CL, Wu TY, Suh N, Yang CS, Kong AN(PubMed)
(7) Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism by Shim M, Eling TE (PubMed)
(8) long-term supplementation with alpha-tocopherol substantially reduced prostate cancer incidence and mortality by Heinonen OP1, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Mäenpää H, Teerenhovi L, Koss L, Virolainen M, Edwards BK.(PubMed)
(9) Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer by Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Morris JS, Comstock GW(PubMed)
(10) Effects of α-tocopherol and β-carotene supplementation on cancer incidence and mortality: 18-Year postintervention follow-up of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study by Virtamo J, Taylor PR, Kontto J, Männistö S, Utriainen M, Weinstein SJ, Huttunen J, Albanes D.(PubMed)
(11) Cancer prevention by different forms of tocopherols by Yang CS, Suh N(PubMed)
(12) Serum α-tocopherol and γ-tocopherol concentrations and prostate cancer risk in the PLCO Screening Trial: a nested case-control study by Weinstein SJ, Peters U, Ahn J, Friesen MD, Riboli E, Hayes RB, Albanes D(PubMed)
(13) Serum and dietary vitamin E in relation to prostate cancer risk by Weinstein SJ, Wright ME, Lawson KA, Snyder K, Männistö S, Taylor PR, Virtamo J, Albanes D.(PubMed)
(14) Serum alpha-tocopherol and gamma-tocopherol in relation to prostate cancer risk in a prospective study by Weinstein SJ, Wright ME, Pietinen P, King I, Tan C, Taylor PR, Virtamo J, Albanes D(PubMed)
(15) Associations between alpha-tocopherol, beta-carotene, and retinol and prostate cancer survival by Watters JL, Gail MH, Weinstein SJ, Virtamo J, Albanes D(PubMed)
(16) Mediterranean Diet and Prostate Cancer Risk and Mortality in the Health Professionals Follow-up Study by Kenfield SA, Dupre N, Richman EL, Stampfer MJ, Chan JM, Giovannucci EL.(PubMed)
(17)  A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii by Severson RK, Nomura AM, Grove JS, Stemmermann GN.(PubMed)
(18) Alcohol consumption, smoking, and other risk factors and prostate cancer in a large health plan cohort in California (United States) by Hiatt RA, Armstrong MA, Klatsky AL, Sidney S.(PubMed)




Breast cancer in Vitamin B12's Points of View

 Kyle J. Norton(Draft article)

Vitamin B12, also known as cobalamin, is a water-soluble vitamin, found abundantly in found in a variety of foods, such as fish, shellfish, meat, eggs, dairy products, etc. and plays an important role in regulating the functions of nervous system and formation of blood.
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 linking levels of plasma of vitamin B12 in reduced risk of breast cancer have produced inconclusive results. In premenopausal women, Plasma vitamin B(12) levels were inversely associated with breast cancer risk(1)(1a)(1b)(1c). Unfortunately, in the study of the same, showed vitamin B-12, may confer little or no reduction in overall risk of developing breast cancer (2)(3)(3a).
In human breast cancer cell line, MCF-7 and normal mammary cells, MCF-10A, lipotropes containing methionine, choline, folate, and vitamin B12, showed an decrease of expression of bcl-2 in regulating apoptosis in lipotrope-treated MCF-7 cells of these suggestion of blocking  Bcl-2 might prove useful in sensitizing tumor cells to chemotherapy-induced apoptosis(4). In rat fed with  Lipotropes showed a reduction of tumor multiplicity and tumor volume significantly through decreased expression of histone deacetylase 1 (Hdac1) and DNA methyltransferase 1 (Dnmt1) genes in tumor tissues of the rats(5). In the study of Maternal high-methyl diet, Lipotropes showed significantly decreased tumor incidence, tumor multiplicity and tumor volume, while also displaying a significant increase in survival rate and tumor latency in rat offspring(6) and enhanced the efficacy of chemo durgs, SAHA and DOX through induced apoptosis, inhibited cell growth, and displayed anti-proliferation(7).

Taking all together, one can say the effective if vitamin B12 in reduced risk of breast cancer and enhanced the efficacy of chemo-drugs was found in conjunction with other members of the methyl group but not the vitamin itself. Over doses of the vitamin may induce symptoms of toxicity, including headache, giddiness and abnormal heart functioning, etc., please make sure to follow the guideline of the Institute of Medicine of the National Academies.
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References
(1) Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer by Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA, Hankinson SE.(PubMed)
(1a) 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)
(1b) Dietary intake of folate, B-vitamins and methionine and breast cancer risk among Hispanic and non-Hispanic white women by Yang D, Baumgartner RN, Slattery ML, Wang C, Giuliano AR, Murtaugh MA, Risendal BC, Byers T, Baumgartner KB.(PubMed)
(1c) 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)
(2) 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)
(3) Plasma folate, vitamin B6, vitamin B12, and homocysteine and pancreatic cancer risk in four large cohorts by Schernhammer E, Wolpin B, Rifai N, Cochrane B, Manson JA, Ma J, Giovannucci E, Thomson C, Stampfer MJ, Fuchs C.(PubMed)
(3a) Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial by Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE.(PubMed)
(4) Lipotropes regulate BCL-2 gene expression in the human breast cancer cell line, MCF-7 by Hyung H. Kim, Chung S. Park(PubMed)
(5) Pubertal supplementation of lipotropes in female rats reduces mammary cancer risk by suppressing histone deacetylase 1 by Cho K, Choi WS, Crane CL, Park CS.(PubMed)
(6) Maternal high-methyl diet suppresses mammary carcinogenesis in female rat offspring by Cho K, Mabasa L, Bae S, Walters MW, Park CS.(PubMed)
(7) Lipotropes enhance the anti-proliferative effect of chemotherapeutic drugs in MCF-7 human breast cancer cells by Cho K, Mabasa L, Walters MW, Park CS.(PubMed)