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Sunday, 23 February 2014

Prostate Cancer in Points of View of Foods, Herbs and Vitamins



By Kyle J. Norton



I. In Foods' Points of View
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. 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. Foods 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.
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.

A. Types of vegetables may reduce risk of Prostate cancer
1. Cruciferous vegetables
Cruciferous vegetables are the group of vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc..
Epidemiological studies has demonstrated reduced risk of prostate cancer in cruciferous consumption. Indole-3-carbinol,  a major chemical compound in Crucifers, are found to be effective in  inhibiting prostate cancer by blocking initiation through induction of phases I and II detoxification pathways and suppressing prostate cancer progression, through down-regulated cell signaling pathways(1). Its derivative 3,3'-Diindolylmethane (DIM), showed to activate the AMPK(regulator of cellular energy homeostasis) signaling pathway, associated with suppression of the mammalian target of rapamycin (mTOR)(cell regulator), down-regulation of androgen receptor (AR) expression, and induction of apoptosis in both androgen-sensitive prostate cancer cells(2). Erucin (ER), derived from  Isothiocyanates (ITCs) in crucifers, may hold an anti progressive property in prostate cancer as it showed an effect in increasing significantly p21 protein expression ( regulator of cell cycle progression at G1 and S phase) and ERK1/2 phosphorylation(cell regulation) in a dose-dependent manner to inhibit PC3(Human prostate cell line) cell proliferation(3). Sulforaphane (SFN)  in crucifers also inhibited prostate cancer cell line through impacting epigenetic pathways(4).

2. Tomato
Tomato is a red, edible fruit, genus Solanum, belonging to family Solanaceae, native to South America. Because of its health benefits, tomato is grown world wide for commercial purpose and often in green house.
Studies of tomato, linking to reduced risk of prostate caner have produced inconsistent results.(5)(6)(7)(8)(9). Regardless to these mixed results, intake of lycopene and specific tomato products acknowledged by many researchers is associated in reduced risk  prostate cancer. Lycopene, a lipid soluble carotenoid molecule found in tomato and Alpha (α)-tomatine, a saponin presented in tomato, showed to exert its tumor suppressing effects by increased apoptosis and lower proliferation of tumor cells.(10)(11). According to the Northwestern University Medical School, in a recent prospective dietary analysis identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer(12)(13). In Androgen-independent DU145 prostate cancer cells, Apo-lycopenals or other lycopene metabolites, significantly reduced cell proliferation through alteration of the normal cell cycle(14). In BALB/c nude mice, lycopene caused DU145 cells to accumulate in the G(0)/G(1) (Cell cycle)phase and to undergo apoptosis in a dose-dependent manner(15).

3. Garlic
Garlic is a natural superfood healer for its natural antibiotic with antiviral, antifungal, anticoagulant and antiseptic properties.
Garlics intake, are related to decreased risk of prostate cancer(17), in a reviewed study with evidence from 132,192 subjects(18). S-allylcysteine (SAC) derived from garlic, suppressed the proliferation of PC-3 cells and led to cell cycle arrest at the G0/G1 Cell cycle)phases, as well as inducing cell apoptosis which was accompanied by the decreased expression of Bcl-2 and increased expression of Bax and caspase 8(19). Diallyl disulfide (DADS) another compound in garlic, at 25 and 40 microM concentrations  induced cell cycle arrest and  apoptosis in PC-3 cells through increased expression of caspases(extent of apoptosis)(20) (3, 9, and 10), proapoptotic protein Bax(Apoptosis regulator)(21).

4. Sweet potato
Sweet potato is a large, starchy, sweet tasting tuberous roots vegetable, genus Ipomoea, belonging to the family Convolvulaceae. Its young leaves can be made into a delicious dish in Chinese foods but some species of batatas are actually poisonous.
Sweet potato (Ipomoea batatas) leaves, a favor vegetable consumed extensively in Africa and Asia, containing rich sources of dietary polyphenols (anthocyanins and phenolic acids) exerted its significant antiproliferative activity in some prostate cancer cell lines without damaging to normal prostate epithelial cells.  SPGE (Sweet potato extract) altered cell cycle progression, reduced clonogenic survival, modulated cell cycle and apoptosis regulatory molecules and induced apoptosis in human prostate cancer PC-3 cells both in vitro and in vivo(22).  In nude mice testing, the extract inhibited growth and progression of prostate tumor xenografts by ~75%(23).

5. Ginger
Ginger (Zingiber officinale) or ginger root is the genus Zingiber, belonging to the family Zingiberaceae, native to Tamil. It has been used in traditional and Chinese medicine to treat dyspepsia, gastroparesis, constipation, edema, difficult urination, colic, etc.
Ginger extract (GE) and 6-gingerol. a chemical constituent found in ginger root, synergistically inhibited proliferation of PC-3 cells(24). Daily oral feeding of 100 mg/kg body weight of GE, inhibited growth and progression of PC-3 xenografts by approximately 56 % in nude mice and reduced proliferation index and widespread apoptosis compared with controls(25). In the comparison of GE and an artificial quasi-mixture (Mix) formulated by combining four most-active ginger constituents at concentrations equivalent,  GE showed 2.4-fold higher tumor growth-inhibitory efficacy than Mix in human prostate tumor xenografts(26).

6. Spinach
Suggestion of intake of typical green and yellowvegetable and  spinach were associated to reduced risk factors for prostate cancer(27) and risk of aggressive prostate cancer decreased with increasing spinach consumption(28). Spinach extract (NAO) exerted its anti profileration of the human PCA cell line PC3 by NAO-induced G1 delay and prolonged cell cycle prolongation as a result of downregulation of the protein expression of ppRb(tumour suppressor pathway)(29)and E2F transcription factors(30). In human prostatic cancer (PCA) cell lines DU145 and PC3, showed an inhibition of cellular proliferation occurred in a dose-dependent manner, increasing numbers of G1 cells (Cell cycle)and reducing ROS(reactive oxygen species) levels(31).

7. Chili pepper
Chili pepper is the fruit of plants from the genus Capsicum, belonging to the nightshade family, Solanaceae. The fruit has been used in human history for spices and cultivated for commercial profits.
Capsaicin, a chemical constituent of chili pepper exerted its antiproliferative activity correlates with oxidative stress induction and apoptosis and potently suppresses the growth of human prostate carcinoma cells in vitro and in vivo(32), inducing the apoptosis of both androgen receptor (AR)-positive (LNCaP) and -negative (PC-3, DU-145) prostate cancer cell lines associated with an increase of p53, p21, and Bax(33)(34). Capsaicin in other study showed to induce apoptosis in PC-3 cells(Prostate cancer) via ROS(reactive oxygen species) generation, JNK(tumorigenetic regulator) activation, ceramide accumulation, and second, extracellular signal-regulated protein kinase (ERK) activation(35).

8. Carrot
Studies of Dietary intake of the carotenoids beta-carotene and lycopene found in carrot for its reduced risk of prostate cancer has produced inconsistent results. Some studies suggested that dietary intake of beta-carotene and its main vegetable sources was largely unassociated with prostate cancer risk, whereas intake of lycopene and tomato-based foods was weakly associated with a reduced risk(36). In antioxidant study, some researchers suggested that beta-carotene supplementation in men with low dietary beta-carotene intakes were associated with reduced risk of prostate cancer(37) and vegetable and carotene intake was associated with lower risk of prostate cancer among Japanese(38). Unfortunately, there is a report of intake of beta-carotene supplement may increase prostate cancer incidence, 23% higher and mortality, 15% higher in comparison with those not receiving(39).

9. Mushroom 
Mushroom is a standard name of white button mushroom, the fleshy, spore-bearing fruiting body of a fungus produced above ground on soil or on its food source, It is a genus A. Muscaria, belonging to the family Amanitaceae and has been cultivation in many cultures all over the world for foods and health benefits.
Mushroom Inonotus obliquus (I. obliquus) petroleum ether and ethyl acetate fractions was found  effectively against human prostate cancer cell line PC3  by inhibition effects on NO production and NF-κB luciferase activity in cells produced by the differentiation of  white blood cells in RAW 264.7 cells and cytotoxicity(40). Also in human androgen-independent cancer PC-3 cells, water-soluble extract (POE) of the fresh oyster mushroom exerted most significant cytotoxicity on PC-3 cells comparisin to 2 other mushroom species with cytotoxicity and induced apoptosis mediated in dose-dependent manner(41). Polysaccharide-K® (PSK), an extract of the mushroom, induced significantly tumor suppression in a reduction of tumor proliferation and  apoptosis enhanced, by lowering the decrease in number of white blood cells, accompanied by increased numbers of tumor-infiltrating CD4+ and CD8+ T cells.(42).

10. Bean sprouts
eaten raw or cooked, bean sprouts are common ingredient in Asian cuisine, made from sprouting beans.
Isoliquiritigenin isolated from bean sprout, used in treatment on the migration, invasion and adhesion characteristics of DU145 human prostate cancer showed to inhibit basal and EGF-induced cell(proliferation) migration, invasion in doses dependent(43) and cell proliferation and induced apoptosis in DU145 human prostate cancer cells and MAT-LyLu (MLL) rat prostate cancer cells, through inhibition of ErbB3 signaling and the PI3K/Akt ((anti-apoptosis and increased cell proliferation)pathway(44). Other researchers also suggested that these inhibition are associated with an evident disruption of the mitochondrial membrane potential, and the release of cytochrome c and Smac/Diablo(a mitochondrial protein), and the activation of caspase-9(apoptosis)(45).

B. Types of fruit may reduce risk of prostate cancer
1. Mangosteen fruit
Mangosteen fruit, a tropical fruit growth in South East Asia is a tropical evergreen tree originated in the Sunda Islands and the Moluccas of Indonesia.
In 22Rv1 and LNCaP, and prostate epithelial cells (PrECs), standardized mangosteen fruit extract (MFE), showed its inhibited effect by suppressing tumor growth in a xenograft tumor model without causing damage to non-tumorigenic prostate epithelial cell and induced toxicity(46). Polyphenols, the main chemical constituent of the fruit extract also targeted multiple signaling pathways involved in cell cycle modulation and apoptosis in prostate cancer(47). α-Mangostin, a xanthone derived from Polyphenols of mangosteen fruit, targeted cell cycle-related proteins involved in prostate carcinogenesis(48).

2. Long Pepper or Indian long pepper

Used as a spice and seasoning, Long Pepper or Indian long pepper is a flowering vine in the family Piperaceae.
Piperlongumine (PL), a natural alkaloid presented in the fruit of the Long pepper, exerted its effect on prostate cancer by downregulation of Akt downstream signaling(apoptosis, cell proliferation) resulted in decrease of mTORC1 (nutrient/energy)activity and autophagy (cell degradation)stimulation(49). PL also found to induce rapid depletion of the Androgen receptor (AR) in prostate cancer (PC) cells which is an early indication of prostate cancer(50). In human prostate cancer DU145, PC-3 and LNCaP cells, piperine, another an alkaloid from black and long peppers, exhibited anti-proliferative effect in human prostate cancer cells by inducing cell cycle arrest and autophagy(51).

3. Pomegranate
Pomegranates is a fruit-bearing small tree, genus Punica, belonging to family Lythraceae, native to Iran but has been cultivated in Asian since ancient time.
POMx, a omegranate (PE) formula currently approved for clinical trials, effectively inhibited survivin (baculoviral inhibitor), induced apoptosis, retarded the rate of tumor growth in skeleton(52).
Polyphenols, main chemical compounds from pomegranate fruit extracts (PFEs), slightly decreased secretion of matrix metalloproteinase (MMP)-2 but not MMP-9 (expression usually seen in invasive and highly tumorigenic cancers) from both prostate cell lines(53). Other polyphenol derivative, ellagic acid (EA) than to urolithin (UA) converted from Ellagitannins (ETs) from pomegranate juice (PJ), sgnificantly decreased cell proliferation by exhibiting synergism in PC-3 cells(54).

4. Strawberry
Strawberries is a genius of Fragaria × ananassa belongs to the family Roseaceae. They have been grown all over the world with suitable climate for commercial profits and for health benefits.
Berry juice study, including strawberry, showed to inhibit prostate cancer cell proliferation, not involve caspase-dependent apoptosis, but in cell-cycle arrest, by down-regulation of the expression of cdk4, cdk6, cyclin D1 and cyclin D3(Decrease the proliferative activity (55). In fact  major classes of berry phenolics, including anthocyanins, flavonols, flavanols, ellagitannins, gallotannins, proanthocyanidins, and phenolic acids are found to be effective in inhibition the growth of many human cancer cell lines, including prostate (LNCaP) tumor cell lines at concentrations ranging from 25 to 200 micro g/mL.(56).  Crude  extracts (250 microg/mL) from strawberry and its pure compounds (100 microg/mL)also found to inhibit prostate (LNCaP, DU145) cancer cells(57).

5. Grapes 
Grape is a woody vines of the genus Vitis, belong to the family Vitaceae, native to southern Turkey.
Fisetin, a chemical compound found in grape inhibited prostate cancer cell lines through downregulation of the PI3K/Akt (anti-apoptosis and increased cell proliferation)and the mTOR(energy sources) pathways(58). Another chemical constituent  pterostilbene, in dose-dependent inhibited cellular proliferation, through activation of expression of AMPK(cellular energy homeostasis) and the p53(antigens) but in p53 positive LNCaP cells, pterostilbene blocked the progression of cell cycle at G1 phase by inducing p53 expression and further up-regulating p21 expression and  in p53 negative, induced apoptosis in PC3 cells(59). Piceatannol found in grape, exhibited potential anticancer properties by suppressing proliferation of a wide variety of tumor cells, through cell-cycle arrest, upregulation of antibody antigens and  apoptotic activity and down-regulation of cancer cell proliferation(60).

6. Apple
Apple is the pomaceous fruit of the apple tree, a species of the rose family Rosaceae. It is one of the most widely cultivated tree fruits. The tree is originated in Central Asia.
Apple peel extract (APE), exerted its anti cancer effects by significant decreasing in growth and enhancing clonogenic survival of human prostate carcinoma CWR22Rnu1 and DU145 cells, through a G0-G1(Cell cycle) phase arrest(61). In the study of Does an apple a day keep the oncologist away? showed an inverse association of apple intake and incidence of cancer(62).

7. Papaya
Papaya is a species of Carica Papaya, belongs to the family Caricaceae and native to the tropics of the Americas, and was first cultivated in Mexico and several centuries.
Benzylisothiocyanate (BITC), a solvent of papaya fruit inhibited cancer cell line through induced apoptosis by converging two major pathways: the death receptor mediated extrinsic and the mitochondrial intrinsic pathway(63). In the role of diet, papaya is found effectively (more than 22.7 g/d (50th percentile) in reduced prostate cancer risk by 7.4 (Adjusted OR 7.4 (95% CI 1.17-46.8)(64). Lycopene, a major chemical constituent in tomato, also in papaya, in prospective and retrospective epidemiological studies indicated of an inverse relationship between lycopene intake and prostate cancer risk in vitro and in vivo experiments(65).

8. Apricot 
Apricot tree is about 8–12 m tall and a trunk up to 40 cm diameter belonging to the family Rosaceae. Apricot is classified with the family of the plum and has yellow to orange, often tinged red on the side which is exposed to the sun.
Ethanolic extracts (30%) of apricot showed to inhibit  the growth of PC-3 and LNCaP (Prostate cancer cell lines) cells; induce apoptosis and alter cell kinetics; down regulated ERalpha (estrogen receptor α), ) and PKC-alpha(interaction with the cell membrane) protein, and demonstrate good binding ability to both mouse uterine estrogen receptors and LNCaP human androgen receptors(66).

 9. Avocado 
Avocados are a commercially valuable fruit and are cultivated in tropical climates throughout the world, it is a green-skinned, pear-shaped fruit that ripens after harvesting and native to the Caribbean, Mexico, South America.
Whole-blood fatty acids testing indicated that higher intakes of dietary MUFA(monounsaturated fatty) with principal source of dietary avocado intake was inversely related to prostate cancer(67).
Acetone extract of avocado, containing carotenoids and tocopherols showed to inhibit the growth of both androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines in vitro. Incubation of PC-3 cells with the avocado extract led to G(2)/M cell cycle arrest accompanied by an increase in p27(cell cycle inhibitor) protein expression(68).

10. Citrus fruits
Fruits of the genus Citrus, native to southern and southeast Asia, include grapefruit, lemon, orange, etc.
Study of incidence of prostate caner in North India compared to South India, showed a positive decreased risk of increasing dietary consumption of tea, citrus fruits and melon(69). Citrus consumption is associated with reduced all-cancer incidences, according to the study of cancer incidence among 42,470 Japanese adults in the Ohsaki National Health Insurance Cohort(70). Oral administration of Gold Lotion (GL), an extract of multiple varieties of citrus peels containing abundant flavonoid, showed the deduction of both the weights (57%-100% inhibition) and volumes (78%-94% inhibition) of the tumors without any adverse toxicity, accompanied by mechanistic down-regulation of the protein levels of inflammatory enzymes (inducible nitric oxide synthase, iNOS and cyclooxygenase-2, COX-2), metastasis (matrix metallopeptidase-2, MMP-2 and MMP-9), angiogenesis (vascular endothelial growth factor, VEGF), and proliferative molecules, as well as by the induction of apoptosis in prostate tumors(71). Unfortunately, some studies did not show an association between intake of citrus fruits and the risk of prostate cancer(72).

11. Bitter melon 
Bitter melon, a extremely bitter fruit, is a tropical and subtropical vine  belonging to the family Cucurbitaceae, native in Asia, Africa, and the Caribbean. Treatment of bitter melon extract (BME) in prostate cancer, enhanced Bax expression(involved in p53-mediated apoptosis) and induced PARP(a nuclear protein implicated in DNA repair) cleavage(during apoptosis), delayed the progression to high-grade prostatic intraepithelial neoplasia (precede the development of prostate adenocarcinoma) and displayed approximately 51% reduction of proliferating cell nuclear antigen expression in mice(73). MCP30, from bitter melon seeds induced apoptosis in PIN and PCa cell lines in vitro and suppressed PC-3 growth in vivo with no effect on normal prostate cells(74). Bitter melon leaf extract (BMLE) inhibited the secretion of MMP-2, MMP-9(metastasis) and urokinase plasminogen activator (uPA)(invasion and metastasis) from rat prostate cancer cell line (PLS10)(75).

C. Others

1. Flaxseed
Flax seed is native to the region of the eastern Mediterranean to India and also known as common flax or linseed. Flax is an erect annual plant, it can grow to 1.2 m tall. The leaves are 20–40 mm long and 3 mm broad.
Enterolactone and enterodiol, mammalian lignans derived from dietary flaxseed may obstruct or delay the progressed prostate cancer cell proliferation via vascular endothelial growth factor(VEGF)-associated pathways(76). Other study indicated that diet supplemented with 5% flaxseed inhibits the growth and development of prostate cancer in the TRAMP model(77) and  Flaxseed-supplemented  diet showed to lower prostate cancer proliferation rates and associated with biological alterations that may be protective for prostate cancer(78).

2. Vegetable oil 
Vegetables oil is a triglyceride extracted from a plant.
Increased levels of MUFA-rich vegetable oil((including olive oil, canola or peanut oil)) intake were associated with a progressive reduction in prostate cancer risk(79). Hydrogenated soybean oil (SHSO) showed remarkably strong anticarcinogenic activity against prostate cancer in the rat model and 5% dietary supplementation with SHSO inhibited the growth of prostate cancer by 80% in vivo(80).

3. Honey
The rich golden liquid is the miraculous product made by bees using nectar from flowers. It is considered as one of healthy sweet food for replacing the use of white sugar and artificial sweetener by many people.
Chrysin, a natural flavone commonly found in honey, and honey itself showed to exert its antiproliferative effect on PC-3 cells in a dose- and time-dependent manner(81)

4. Chickpea
Garbanzo beans also known as chickpea is an edible legume of genus Cicer and the family Fabaceae, high in protein and minerals. It is one of the earliest cultivated vegetables, native to Middle East.
7 protease inhibitor concentrates (PICs) isolated from chickpea showed a significant inhibition the LNCaP prostate cancer cells in concentrations tested of 25-400 μg/ml(82).

5. Olive oil
Extra virgin olive oil (EVOO), was found to significantly affect the growth of HCT 116 tumours xenografted in athymic mice(83). Polyphenols, found in Extra virgin olive oil (EVOO), exerted chemopreventive effects towards different organ specific cancers, affecting the overall process of carcinogenesis by inhibition of DNA synthesis, modulation of ROS production, regulation of cell cycle arrest, modulation of survival/proliferation pathways(84). Other study suggested that Polyphenols can directly interact with specific steps and/or proteins regulating the apoptotic process in different ways depending on their concentration, the cell system, the type or stage of the pathological process(85).

6. Black pepper
Black pepper, is a flowering vine in the family Piperaceae, its fruits used as a spice and seasoning
Piperine, a major alkaloid constituent of black pepper, inhibited the proliferation of LNCaP, PC-3, 22RV1 and DU-145 prostate cancer cells in a dose dependent manner and induced apoptosis resulted in caspase activation in LNCaP and PC-3 cells(86). β-caryophyllene oxide (CPO), a sesquiterpene isolated from essential oils of medicinal plants such as guava (Psidium guajava), oregano (Origanum vulgare L.), cinnamon (Cinnamomum spp.) clove (Eugenia caryophyllata), and black pepper (Piper nigrum L.) not only inhibited the constitutive activation of PI3K/AKT/mTOR/S6K1 (anti-apoptosis and increased cell proliferation and nutrient–hormonal signaling network) pathway signaling cascade but also down-regulated the expression of various downstream gene products that mediate cell proliferation (cyclin D1), survival (bcl-2, bcl-xL, survivin, IAP-1, and IAP-2), metastasis (COX-2), angiogenesis (VEGF), and increased the expression of p53 and p21(87).

7. Green tea
Green tea containing more amount of antioxidants than any drinks or food with the same volume, is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
Green tea catechins (GTCs), a potent chemical constituent containing (-)-epigallocathechin,  (-)-epicatechin, (-)-epigallocatechin-3-gallate, (-)-epicatechin-3-gallate, in treatment of preprostate cancer men reduced lower urinary tract symptoms, improved coexistent benign prostate hyperplasia and reached a statistical significance in the case of International Prostate Symptom Scores(88).
In green tea polyphenols study, epigallocatechin-3-gallate (EGCG) exerted its anti cancer effect on signaling pathways in PCa(89). Also combination admiration of quercetin and green tea, showed a significant increase in the inhibition of proliferation, androgen receptor and phosphatidylinositol 3-kinase/Akt signaling(tumor genesis in early stage), and stimulation of apoptosis(90). In short, Green tea, a potent anti prostate cancer with activities of heritable alterations of gene expression and chromatin organization without changes in DNA sequence induced multistep process of carcinogenesis(91) may be considered as a natural treatment in vary types of cancer.

8. Fermented soybean products
Fermented soybean products are made from fermenting soybeans and filamentous fungus, along with water and salt after a period of sometime.
In the Japan, incidence of prostate caner in aging men are low compared with the Western world, suggestion of these result may be tradition Japanese diet related.  Consumption of fish, all soybean products, tofu (bean curds), and natto (fermented soybeans) was associated with decreased risk of ORs (Estimates of age-adjusted odds ratios) which supported traditional Japanese diet rich in soybean products and fish against prostate cancer(92). In China, suggestion of reduced risk of prostate cancer associated with consumption of soy foods and isoflavones found abundantly in fermented soybean products(93). Unfortunately, the epidemiological data, linking ferment soybean products to reduced risk of prostate cancer are inconsistent including miso.

The prevalence and widespread of prostate cancer may be diet, demographic and life style related disease(94)(95)(96). Suggestions and intentions are for prevention of prostate cancer to develop in the first place or used conjunction with conventional medicine in treating the disease. Eating healthy, with plenty of vegetables and fruits has always been considered as a preventive engagement in human history. "Let foods be your medicine and let medicine be your foods" by Greek physician Hippocrates (460-377 BC).

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References
(1) Phytochemicals from cruciferous vegetables, epigenetics, and prostate cancer prevention by W Watson G, M Beaver L, E Williams D, H Dashwood R, Ho E.(PubMed)
(2) Activation of AMP-activated protein kinase by 3,3'-Diindolylmethane (DIM) is associated with human prostate cancer cell death in vitro and in vivo by Chen D, Banerjee S, Cui QC, Kong D, Sarkar FH, Dou QP.(PubMed)
(3) Antiproliferative activity of the dietary isothiocyanate erucin, a bioactive compound from cruciferous vegetables, on human prostate cancer cells by Melchini A, Traka MH, Catania S, Miceli N, Taviano MF, Maimone P, Francisco M, Mithen RF, Costa C.(PubMed)
(4) Promoter de-methylation of cyclin D2 by sulforaphane in prostate cancer cells by Hsu A, Wong CP, Yu Z, Williams DE, Dashwood RH, Ho E.(PubMed)
(5) Low prostate concentration of lycopene is associated with development of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia by Mariani S1, Lionetto L2, Cavallari M3, Tubaro A4, Rasio D5, De Nunzio C6, Hong GM7, Borro M8, Simmaco M9.(PubMed)
(6) A prospective study of tomato products, lycopene, and prostate cancer risk by Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC.(PubMed)
(7) A prospective study of lycopene and tomato product intake and risk of prostate cancer by Kirsh VA, Mayne ST, Peters U, Chatterjee N, Leitzmann MF, Dixon LB, Urban DA, Crawford ED, Hayes RB(PubMed)
(8) Lycopene/Tomato consumption and the risk of prostate cancer: a systematic review and meta-analysis of prospective studies by Chen J, Song Y, Zhang L.(PubMed)
(9) The role of tomato products and lycopene in the prev29ntion of prostate cancer: a meta-analysis of observational studies by Etminan M, Takkouche B, Caamaño-Isorna F.(PubMed)
(10) Alpha-tomatine attenuation of in vivo growth of subcutaneous and orthotopic xenograft tumors of human prostate carcinoma PC-3 cells is accompanied by inactivation of nuclear factor-kappa B signaling by Lee ST, Wong PF, He H, Hooper JD, Mustafa MR.(PubMed)
(11) Alpha-tomatine induces apoptosis and inhibits nuclear factor-kappa B activation on human prostatic adenocarcinoma PC-3 cells by Lee ST, Wong PF, Cheah SC, Mustafa MR.(PubMed)
(12) Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis by Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer MJ.(PubMed)
(13) Inverse associations between plasma lycopene and other carotenoids and prostate cancer by Lu QY, Hung JC, Heber D, Go VL, Reuter VE, Cordon-Cardo C, Scher HI, Marshall JR, Zhang ZF.(PubMed)
(14) Lycopene and apo-12'-lycopenal reduce cell proliferation and alter cell cycle progression in human prostate cancer cells by Ford NA, Elsen AC, Zuniga K, Lindshield BL, Erdman JW Jr.(PubMed)
(15) Lycopene inhibits the growth of human androgen-independent prostate cancer cells in vitro and in BALB/c nude mice by Tang L, Jin T, Zeng X, Wang JS.(PubMed)
(16) Allium vegetables and risk of prostate cancer: evidence from 132,192 subjects by Zhou XF, Ding ZS, Liu NB.(PubMed)
(17) Allium vegetables and risk of prostate cancer: a population-based study by Hsing AW, Chokkalingam AP, Gao YT, Madigan MP, Deng J, Gridley G, Fraumeni JF Jr.(PubMed)
(18) Allium vegetables and risk of prostate cancer: a population-based study by Hsing AW, Chokkalingam AP, Gao YT, Madigan MP, Deng J, Gridley G, Fraumeni JF Jr.(PubMed))
(19) S-allylcysteine induces cell cycle arrest and apoptosis in androgen-independent human prostate cancer cells by Liu Z, Li M, Chen K, Yang J, Chen R, Wang T, Liu J, Yang W, Ye Z(PubMed).
(20) Expression of caspases 3, 6 and 8 is increased in parallel with apoptosis and histological aggressiveness of the breast lesion by Vakkala M, Pääkkö P, Soini Y.(PubMed)
(21) Effects of diallyl disulfide (DADS) on expression of apoptosis associated proteins in androgen independent human prostate cancer cells (PC-3) by Gayathri R, Gunadharini DN, Arunkumar A, Senthilkumar K, Krishnamoorthy G, Banudevi S, Vignesh RC, Arunakaran J.(PubMed)
(22) Polyphenol-rich sweet potato greens extract inhibits proliferation and induces apoptosis in prostate cancer cells in vitro and in vivo by Karna P, Gundala SR, Gupta MV, Shamsi SA, Pace RD, Yates C, Narayan S, Aneja R.(PubMed)
(23) Polar biophenolics in sweet potato greens extract synergize to inhibit prostate cancer cell proliferation and in vivo tumor growth by Gundala SR, Yang C, Lakshminarayana N, Asif G, Gupta MV, Shamsi S, Aneja R.(PubMed)
(24) Ginger phytochemicals exhibit synergy to inhibit prostate cancer cell proliferation by Brahmbhatt M, Gundala SR, Asif G, Shamsi SA, Aneja R.(PubMed)
(25) Benefits of whole ginger extract in prostate cancer by Karna P, Chagani S, Gundala SR, Rida PC, Asif G, Sharma V, Gupta MV, Aneja R.(PubMed)
(26) Enterohepatic re-circulation of bioactive ginger phytochemicals is associated with enhanced tumor growth-inhibitory activity of ginger extract by Gundala SR, Mukkavilli R, Yang C, Yadav P, Tandon V, Vangala S, Prakash S, Aneja R.(PubMed)
(27) A case-control study of prostatic cancer with reference to dietary habits by Oishi K, Okada K, Yoshida O, Yamabe H, Ohno Y, Hayes RB, Schroeder FH.(PubMed)
(28) Prospective study of fruit and vegetable intake and risk of prostate cancer by Kirsh VA, Peters U, Mayne ST, Subar AF, Chatterjee N, Johnson CC, Hayes RB; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.(PubMed)
(29) Enterohepatic re-circulation of bioactive ginger phytochemicals is associated with enhanced tumor growth-inhibitory activity of ginger extract by Gundala SR, Mukkavilli R, Yang C, Yadav P, Tandon V, Vangala S, Prakash S, Aneja R.(PubMed)
(30) Unique natural antioxidants (NAOs) and derived purified components inhibit cell cycle progression by downregulation of ppRb and E2F in human PC3 prostate cancer cells by Bakshi S, Bergman M, Dovrat S, Grossman S.(PubMed)
(31) Slowing tumorigenic progression in TRAMP mice and prostatic carcinoma cell lines using natural anti-oxidant from spinach, NAO--a comparative study of three anti-oxidants by Nyska A, Suttie A, Bakshi S, Lomnitski L, Grossman S, Bergman M, Ben-Shaul V, Crocket P, Haseman JK, Moser G, Goldsworthy TL, Maronpot RR.(PubMed)
(32) Effect of capsaicin on prostate cancer cells by Díaz-Laviada I.(PubMed)
(33) Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells by Mori A, Lehmann S, O'Kelly J, Kumagai T, Desmond JC, Pervan M, McBride WH, Kizaki M, Koeffler HP.(PubMed)
(34) Capsaicin, a component of red peppers, induces expression of androgen receptor via PI3K and MAPK pathways in prostate LNCaP cells by Malagarie-Cazenave S, Olea-Herrero N, Vara D, Díaz-Laviada I.(PubMed)
(35) Apoptosis induced by capsaicin in prostate PC-3 cells involves ceramide accumulation, neutral sphingomyelinase, and JNK activation by Sánchez AM, Malagarie-Cazenave S, Olea N, Vara D, Chiloeches A, Díaz-Laviada I.(PubMed)
(36) Prostate cancer and dietary carotenoids by Norrish AE, Jackson RT, Sharpe SJ, Skeaff CM.(PubMed)
(37) 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)
(38) Relationship between vegetable and carotene intake and risk of prostate cancer: the JACC study by Umesawa M, Iso H, Mikami K, Kubo T, Suzuki K, Watanabe Y, Mori M, Miki T, Tamakoshi A; JACC Study Group(PubMed)
(39) Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial by Heinonen OP, 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)
(40)Anti-inflammatory and anticancer activities of extracts and compounds from the mushroom Inonotus obliquus by Ma L, Chen H, Dong P, Lu X.(PubMed)
(41)Cytotoxic effect of oyster mushroom Pleurotus ostreatus on human androgen-independent prostate cancer PC-3 cells by Gu YH, Sivam G.(PubMed)
(42) Polysaccharide-K augments docetaxel-induced tumor suppression and antitumor immune response in an immunocompetent murine model of human prostate cancer by Wenner CA, Martzen MR, Lu H, Verneris MR, Wang H, Slaton JW.(PubMed)
(43) Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: possible mediation by decreased JNK/AP-1 signaling by Kwon GT, Cho HJ, Chung WY, Park KK, Moon A, Park JH.(PubMed)
(44) Isoliquiritigenin (ISL) inhibits ErbB3 signaling in prostate cancer cells by Jung JI, Chung E, Seon MR, Shin HK, Kim EJ, Lim SS, Chung WY, Park KK, Park JH.(PubMed)
(45) Isoliquiritigenin induces apoptosis by depolarizing mitochondrial membranes in prostate cancer cells by Jung JI, Lim SS, Choi HJ, Cho HJ, Shin HK, Kim EJ, Chung WY, Park KK, Park JH.(PubMed)
(46) Selective modulation of endoplasmic reticulum stress markers in prostate cancer cells by a standardized mangosteen fruit extract by Li G1, Petiwala SM1, Pierce DR1, Nonn L2, Johnson J(PubMed)
(47) Polyphenols from the mangosteen (Garcinia mangostana) fruit for breast and prostate cancer by Li G, Thomas S, Johnson JJ.(PubMed)
(48) α-Mangostin, a xanthone from mangosteen fruit, promotes cell cycle arrest in prostate cancer and decreases xenograft tumor growth by Johnson JJ, Petiwala SM, Syed DN, Rasmussen JT, Adhami VM, Siddiqui IA, Kohl AM, Mukhtar H.(PubMed)
(49) Piperlongumine promotes autophagy via inhibition of Akt/mTOR signalling and mediates cancer cell death by Makhov P, Golovine K, Teper E, Kutikov A, Mehrazin R, Corcoran A, Tulin A, Uzzo RG, Kolenko VM.(PubMed)
(50) Piperlongumine induces rapid depletion of the androgen receptor in human prostate cancer cells by Golovine KV, Makhov PB, Teper E, Kutikov A, Canter D, Uzzo RG, Kolenko VM.(PubMed)
(51) Piperine inhibits the proliferation of human prostate cancer cells via induction of cell cycle arrest and autophagy by Ouyang DY, Zeng LH, Pan H, Xu LH, Wang Y, Liu KP, He XH.(PubMed)
(52) Pomegranate extract inhibits the bone metastatic growth of human prostate cancer cells and enhances the in vivo efficacy of docetaxel chemotherapy by Wang Y, Zhang S, Iqbal S, Chen Z, Wang X, Wang YA, Liu D, Bai K, Ritenour C, Kucuk O, Wu D.(PubMed)
(53) Ellagic acid inhibits migration and invasion by prostate cancer cell lines by Pitchakarn P, Chewonarin T, Ogawa K, Suzuki S, Asamoto M, Takahashi S, Shirai T, Limtrakul P.(PubMed)
(54) Pomegranate Juice Metabolites, Ellagic Acid and Urolithin A, Synergistically Inhibit Androgen-Independent Prostate Cancer Cell Growth via Distinct Effects on Cell Cycle Control and Apoptosis by Vicinanza R, Zhang Y, Henning SM, Heber D.(PubMed)
(55) Inhibition of cancer cell proliferation and suppression of TNF-induced activation of NFkappaB by edible berry juice by in D, Blanchette M, Barrette S, Moghrabi A, Béliveau R.(PubMed)
(56)Blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human cancer cells in vitro by Seeram NP, Adams LS, Zhang Y, Lee R, Sand D, Scheuller HS, Heber D.(PubMed)
(57)Isolation and identification of strawberry phenolics with antioxidant and human cancer cell antiproliferative properties by Zhang Y, Seeram NP, Lee R, Feng L, Heber D.(PubMed)
(58) Dietary flavonoid fisetin: a novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management by Adhami VM, Syed DN, Khan N, Mukhtar H.(PubMed)
(59) Activation of AMPK by pterostilbene suppresses lipogenesis and cell-cycle progression in p53 positive and negative human prostate cancer cells by Lin VC, Tsai YC, Lin JN, Fan LL, Pan MH, Ho CT, Wu JY, Way TD.(PubMed)
(60) Biological activity of piceatannol: leaving the shadow of resveratrol by Piotrowska H, Kucinska M, Murias M.(PubMed)
(61) Antiproliferative effects of apple peel extract against cancer cells by Reagan-Shaw S, Eggert D, Mukhtar H, Ahmad N.(PubMed)
(62) Does an apple a day keep the oncologist away by Gallus S, Talamini R, Giacosa A, Montella M, Ramazzotti V, Franceschi S, Negri E, La Vecchia C.(PubMed)
(63) Dietary isothiocyanate mediated apoptosis of human cancer cells is associated with Bcl-xL phosphorylation by Basu A, Haldar S.(PubMed)
(64) Roles of diet, lifetime physical activity and oxidative DNA damage in the occurrence of prostate cancer among men in Klang Valley, Malaysia by Shahar S, Shafurah S, Hasan Shaari NS, Rajikan R, Rajab NF, Golkhalkhali B, Zainuddin ZM.(PubMed)
(65) Multitargeted therapy of cancer by lycopene by van Breemen RB, Pajkovic N.(PubMed)
(66) Phytosterol Pygeum africanum regulates prostate cancer in vitro and in vivo by Shenouda NS, Sakla MS, Newton LG, Besch-Williford C, Greenberg NM, MacDonald RS, Lubahn DB.(PubMed)
(67)Associations of whole-blood fatty acids and dietary intakes with prostate cancer in Jamaica by Jackson MD, Walker SP, Simpson-Smith CM, Lindsay CM, Smith G, McFarlane-Anderson N, Bennett FI, Coard KC, Aiken WD, Tulloch T, Paul TJ, Wan RL.(PubMed)
(68)Inhibition of prostate cancer cell growth by an avocado extract: role of lipid-soluble bioactive substances by Lu QY, Arteaga JR, Zhang Q, Huerta S, Go VL, Heber D(PubMed)
(69) A case control study on prostate cancer in Delhi by Tyagi B, Manoharan N, Raina V.(PubMed)
(70) Citrus consumption and cancer incidence: the Ohsaki cohort study by Li WQ, Kuriyama S, Li Q, Nagai M, Hozawa A, Nishino Y, Tsuji I.(PubMed)
(71) Potent anti-cancer effects of citrus peel flavonoids in human prostate xenograft tumors by Lai CS, Li S, Miyauchi Y, Suzawa M, Ho CT, Pan MH.(PubMed)
(72) Citrus fruits intake and prostate cancer risk: a quantitative systematic review by Bae JM, Lee EJ, Guyatt G.(PubMed)
(73) Bitter melon extract impairs prostate cancer cell-cycle progression and delays prostatic intraepithelial neoplasia in TRAMP model by Ru P, Steele R, Nerurkar PV, Phillips N, Ray RB.(PubMed)
(74) Ribosome-inactivating proteins isolated from dietary bitter melon induce apoptosis and inhibit histone deacetylase-1 selectively in premalignant and malignant prostate cancer cells by Xiong SD, Yu K, Liu XH, Yin LH, Kirschenbaum A, Yao S, Narla G, DiFeo A, Wu JB, Yuan Y, Ho SM, Lam YW, Levine AC.(PubMed)
(75) Momordica charantia leaf extract suppresses rat prostate cancer progression in vitro and in vivo by Pitchakarn P, Ogawa K, Suzuki S, Takahashi S, Asamoto M, Chewonarin T, Limtrakul P, Shirai T.(PubMed)
(76) Flaxseed-derived enterolactone is inversely associated with tumor cell proliferation in men with localized prostate cancer by Azrad M, Vollmer RT, Madden J, Dewhirst M, Polascik TJ, Snyder DC, Ruffin MT, Moul JW, Brenner DE, Demark-Wahnefried W.(PubMed)
(77) Effect of flaxseed supplementation on prostatic carcinoma in transgenic mice BY Lin X, Gingrich JR, Bao W, Li J, Haroon ZA, Demark-Wahnefried W.(PubMed)
(78) Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery by Demark-Wahnefried W, Polascik TJ, George SL, Switzer BR, Madden JF, Ruffin MT 4th, Snyder DC, Owzar K, Hars V, Albala DM, Walther PJ, Robertson CN, Moul JW, Dunn BK, Brenner D, Minasian L, Stella P, Vollmer RT.(PubMed)
(79) Men who consume vegetable oils rich in monounsaturated fat: their dietary patterns and risk of prostate cancer (New Zealand) by Norrish AE, Jackson RT, Sharpe SJ, Skeaff CM.(PubMed)
(80) Selectively hydrogenated soybean oil exerts strong anti-prostate cancer activities by Jung MY, Choi NJ, Oh CH, Shin HK, Yoon SH.(PubMed)
(81) Chrysin reduces proliferation and induces apoptosis in the human prostate cancer cell line pc-3 by Samarghandian S, Afshari JT, Davoodi S.(PubMed)
(82)Chickpea (Cicer arietinum) and other plant-derived protease inhibitor concentrates inhibit breast and prostate cancer cell proliferation in vitro. by Magee PJ, Owusu-Apenten R, McCann MJ, Gill CI, Rowland IR.(PubMed)
(83) Analgesic, anti-inflammatory and anticancer activities of extra virgin olive oil by Fezai M, Senovilla L, Jemaà M, Ben-Attia M(PubMed).
(84) Modulatory effects of polyphenols on apoptosis induction: relevance for cancer prevention by D'Archivio M, Santangelo C, Scazzocchio B, Varì R, Filesi C, Masella R, Giovannini C.(PubMed)
(85) Apoptosis in cancer and atherosclerosis: polyphenol activities by Giovannini C, Scazzocchio B, Varì R, Santangelo C, D'Archivio M, Masella R.(PubMed)
(86) Piperine, a Bioactive Component of Pepper Spice Exerts Therapeutic Effects on Androgen Dependent and Androgen Independent Prostate Cancer Cells by Samykutty A, Shetty AV, Dakshinamoorthy G, Bartik MM, Johnson GL, Webb B, Zheng G, Chen A, Kalyanasundaram R, Munirathinam G.(PubMed)
(87) β-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation by Park KR, Nam D, Yun HM, Lee SG, Jang HJ, Sethi G, Cho SK, Ahn KS.(PubMed)
(88) Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study by Bettuzzi S, Brausi M, Rizzi F, Castagnetti G, Peracchia G, Corti A.(PubMed)
(89) Modulation of signaling pathways in prostate cancer by green tea polyphenols by Khan N, Mukhtar H.(PubMed)
(90)Enhanced inhibition of prostate cancer xenograft tumor growth by combining quercetin and green tea by Wang P, Vadgama JV, Said JW, Magyar CE, Doan N, Heber D, Henning SM.(PubMed)
(91) Epigenetic effects of green tea polyphenols in cancer by Henning SM, Wang P, Carpenter CL, Heber D.(PubMed)
(92) A case-control study of diet and prostate cancer in Japan: possible protective effect of traditional Japanese diet by Sonoda T, Nagata Y, Mori M, Miyanaga N, Takashima N, Okumura K, Goto K, Naito S, Fujimoto K, Hirao Y, Takahashi A, Tsukamoto T, Fujioka T, Akaza H.(PubMed)
(93) Soy and isoflavone consumption in relation to prostate cancer risk in China by Lee MM, Gomez SL, Chang JS, Wey M, Wang RT, Hsing AW.(PubMed)
(94) Soy intake and cancer risk: a review of the in vitro and in vivo data by Messina MJ, Persky V, Setchell KD, Barnes S.(PubMed)
(94) 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)
(95)  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)
(96) 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)



II. In Herbs' Points of View

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.
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.
1. Aloe vera
Aloe Vera is species of succulent plant in the genus Aloe, belonging to the Family Xanthorrhoeaceae, native to Sudan. It has become very popular for commercial cultivation due to its health benefits. Aloe vera has been used in herbal medicine in treating many kinds of disease, including wound, burn healing, minor skin infections, sebaceous cysts, diabetes, and elevated of cholesterol, etc. It is also one of many popular herb studied in scientific ways with some conflicted results.
Aloe-emodin, a chemical constituent in Aloe vera, inhibited both proliferation and anchorage-independent growth of PC3 cells through activation of the downstream substrates of mTORC2, Akt and PKCα causes of apoptosis, cell proliferation(1). prostate cancer, LNCaP expression of N-acetylated by cytosolic N-acetyltransferase (NAT) activity and mRNA inhibited by aloe-emodin in doses depending manner through its kinase activity in cellular transformation(2)(3).

2. Cascara sagrada
Cascara sagrada is a species of buckthorn, genus Rhamnus, belonging to the family Rhamnaceae, native to western North America, it's bark has been used in traditional medicine for gastrointestinal support. and it is thought to have a laxative and natural cleansing, etc., effect.
Emodin, a cemical compoubd found in Cascara sagrada, inhibited cellular migration and invasion in prostate cancer through downregulate CXCR4 expression which is involved in promoting invasion and metastasis in tumors(4). In human prostate cancer cell LNCaP, amodin increased apoptosis and  decreased in cell proliferation through down regualting the expression of expression of androgen receptor (AR) and prostate specific antigen (PSA) and upregulating the expression of p53(Anti tumor antigen) and p21(( regulator of cell cycle progression at G1 and S phase)(5), In other study, Emodin enhanced the  cytotoxic effectiveness of chemotherapeutic drugs in prostate cancer cells through ROS(reactive oxygen spiecies)-mediated suppression of multidrug resistance and hypoxia inducible factor-1(influence cell metabolism, cell survival and angiogenesis to maintain biological homeostasis)(6).

3. Green tea
Green tea contains more amount of antioxidants than any drinks or food with the same volume, and is the leaves of Camellia sinensis, undergone minimal oxidation during processing, originated from China. Green tea has been a precious drink in traditional Chinese culture and used exceptional in socialization for more than 4000 thousand years. Because of their health benefits, they have been cultivated for commercial purposes all over the world.
Epigallocatechin-3-gallate (Chit-nanoEGCG), a phytochemical in green tea, exerted a significant inhibition of tumor growth and secreted prostate-specific antigen levels compared with EGCG and control groups, trough induction of poly (ADP-ribose) polymerases cleavage, increase in the protein expression of Bax(involved in p53-mediated apoptosis)  with accompanied decrease in Bcl-2(family of regulator proteins that regulate cell death), and activation of caspases(mechanisms of apoptosis) and reduction in Ki-67 and proliferating cell nuclear antigen(7). In androgen-independent prostate cancer, synthetic derivative, EGCG (EGCG-P) and EGCG treatment suppressed the growth of the tumor correlated with the decrease of serum PSA level together with the reduction in tumor angiogenesis and an increase in apoptosis on prostate cancer cells(8). In anticancer drug cisplatin, EGCG ehnaced the effectiveness of the chemo agent in reduction of cell survival of prostate cancer cell line PC3 and induced apoptosis(9).

4. Pomegranate
Pomegranates is a fruit-bearing small tree, genus Punica, belonging to family Lythraceae, native to Iran but has been cultivated in Asian since ancient time.
POMx, a pomegranate extract (PE) formula, exhibited potent in vitro cytotoxicity in metastatic castration-resistant PCa cells through inhibition of survivin, induced apoptosis, retarded C4-2 tumor growth in skeleton and significantly enhanced the efficacy of docetaxel(Chemodrug) in athymic nude mice(10). Ellagic acid (EA) converted from Ellagitannins (ETs) found in from pomegranate juice (PJ) showed to induce apoptosis in both cell lines, DU-145 and PC-3 through induced  cell cycle arrest in S phase associated with decreased cyclin B1 and cyclin D1 levels in regulation of cell cycle progression(11). Pomegranate juice (PJ) PJ components luteolin, ellagic acid, and punicic acid together found to inhibit growth of hormone-dependent and hormone-refractory prostate cancer cells and their migration, increase the expression of cell adhesion genes and decrease expression of genes involved in cell cycle control through suppression microRNAs (miRNAs), decrease several oncogenic miRNAs, and inhibit the chemokines receptor type 4 (CXCR4)/SDF1α chemotaxis axis(decreased PSA cell migration)(12).

6. Garlic
Garlic (Allium sativum) is a species in the onion genus, belonging to family Amaryllidaceae, native to central Asia. It has been used popularly in traditional and Chinese medicine in treating common cold and flu to the Plague, blood pressure cholesterol levels, natural antibiotic, etc.
In androgen-independent prostate cancer, garlic-derived organosulfur compound S-allylmercaptocysteinesuppresses invasion and cell motility of androgen-independent prostate cancer cells via the up-regulation of cell-adhesion molecule E-cadherin(Loss of E-cadherin expression has been implicated in cancer progression and metastasis)(16). Garlic compound diallyl disulfid,a oil soluble organosulfur compound of garlic, exerted its antiproliferative and inhibited effect on prostate cancer cells, through induction of DNA damage in a dose dependent manner(17). Garlic constituent diallyl trisulfide (DATS), induced apoptosis in prostate cancer cells is mediated in part by suppression of XIAP(a protein that stops apoptotic cell death) protein expression(18).

7. Chamomile
Chamomile is also known as camomile, common name of many species daisy-like plants in the family Asteraceae. The herb has been used in traditional medicine as antispasmodic and anti-inflammatory constituents and to treat menstrual cramps and sleep disorders, reduce cramping and spastic pain in the bowels, relieve excessive gas and bloating in the intestine, etc.
Phenolic profile of chamomile showed to inhibited the cell proliferation and to reduce IL-8 (an important mediator of the immune reaction in the innate immune system response) levels in PC3 prostate cancer cells(19). Traditional Botanical Supplement-101 (TBS-101), including the extracts of Panax ginseng, cranberry, green tea, grape skin, grape seed, Ganoderma lucidum and chamomile, showed to inhibit in hormone-refractory PC-3 cells and large aggressive PC-3 tumors cell growth in a dose-dependent manner(20). In human cancer cell lines PC-3, A-549 and MCF-7, Chamomile's essential oils, induced cytotoxicity of prostate carcinoma cell (PC-3), significantly stronger than on human lung carcinoma (A549) and human breast cancer (MCF-7) cell lines(21).

8. Onion
The onion is a close relation of garlic plant in the genus Allium, belonging to the family Alliaceae.  It is often called the "king of vegetables" because of its pungent taste and found in a large number of recipes and preparations, spanning almost the totality of the world's cultures. Depending on the variety, an onion can be sharp, spicy, tangy, pungent, mild or sweet.
Data from southern European populations showed intake of allium vegetables, including onion are  inversely associated reduced  risk of several common cancers, including prostate cancer(22).
 Fisetin, a chemical constituent found in Onion, in prostate cancer, it exerted anti cell profilerative effect as a dual inhibitor of the PI3K/Akt (anti-apoptosis and increased cell proliferation) and the mTOR(regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription) pathways(23). Quercetin, also found in onion, inhibited the prostate cancer line PC-3 through DNA fragmentation and protein expressions of Bcl-2, Bcl-xL, Bax and caspase-3 (cell apoptosis) pathways(24).

9. Turmeric
Turmeric is a perennial plant in the genus Curcuma, belonging to the family Zingiberaceae, native to tropical South Asia. The herb has been used in traditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
In PC-3M prostate cancer cell line, extract from turmeric, showed significant inhibitory effects on anti profilerative ability in PC-3M in clonogenic assays(25). Demethoxycurcumin (DMC), one of mjor chemical constituents found in turmeric, exerted it antitumor effects on prostate cancer cells via AMPK((cellular energy homeostasis))-induced down-regulation of HSP70 (upregulated by and toxic chemicals, particularly heavy metals) and EGFR(over expression of epidermal growth factor receptor  have been associated with a number of cancers)(26)(27). Curcumin, a non-nutritive yellow pigment derived from the turmeric showed a inhibitory effects on the expression of  NF-κB (a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis)correlated with their effects on growth inhibition and apoptosis stimulation in PC-3 cells(28).

10. Ginseng
Ginseng is a slow-growing perennial plants with fleshy roots, the genus Panax, belonging to the family Araliaceae. Depending to the climate where it grows, ginseng can be classified mainly into Panax ginseng Asian ginseng (root), Red ginseng, wild ginseng, American ginseng (root).
In a highly metastatic PC-3M prostate cancer cell line,  Ginsenoside Rg3 (Rg3), a bioactive extract from ginseng, suppressed migration of PC-3M cells by down-regulating AQP1(a molecular water channel protein) expression through p38 (highly expressed in aggressive and invasive cancers)MAPK(Increased MAPK expression and activity in primary human carcinoma) pathway and some transcription factors acting on the AQP1 promoter(29). Ginsenoside 20(S)-Rh2  of Ginsenosides, a main component of ginseng, found to be effective in proliferative inhibition on androgen-dependent and -independent prostate cancer cells(30). Formula of Botanical Supplement-101 (TBS-101), containing Panax ginseng, cranberry, green tea, grape skin, grape seed, Ganoderma lucidum and chamomile showed a significant inhibition of tumor growth and invasion in a dose-dependent manner(31).

11. Grape Seed Extract
Grape Seed Extract is the commercial extracts from whole grape seeds containing many concentrations, including vitamin E, flavonoids, linoleic acid, oligomeric proanthocyanidins(OPCs), etc.. The herb has been used in traditional medicine as antioxidant, anti-inflammatory agents and to treat skin wounds with less scarring, allergies, macular degeneration, arthritis, enhance circulation of blood vessels, lower cholesterol, etc.
Grape seed extract (GSE), inhibited HAT(HAT mutations are associated to certain cancers), leading to decreased AR(plays roles in prostate development and cancer (PCa))-mediated transcription and cancer cell growth, and implicate GSE as a novel candidate for therapeutic activity against prostate cancer(32). B2G2 from total GSE, derived from Procyanidin B2 3,3″-di-O-gallate, a Biologically Active Constituent of Grape Seed Extract inhibited cell growth, decreased clonogenicity(colony expansion), and induced cell cycle arrest and apoptotic death, in various human PCa cell lines(33).
In a highly metastatic androgen-independent PC3 prostate cancer, Grape seed extract (GSE),  inhibited DNA-binding activity of the transcription factor nuclear factor kappa B (NFkappaB)(a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis), which in turn decreased NFkappaB-dependent uPA(in tumor invasion and metastasis) transcription(33).

12. Danshen (Salvia miltiorrhiza Bunge)
Dan Shen is also known as Red Sage Root. The bitter and slightly cold herb has been used in TCM as antithrombotic, antihypertonic (lowering blood pressure), antimicrobial, antipyretic, anti-inflammatory, sedative agent and to treat dysmenorrhea, amenorrhea, palpable tumors, angina,restlessness, insomnia, irritability, etc., by enhancing the functions of heart and liver channels.
Tanshinones, a chemical constituent found in Chinese herb Dan Shen, was found to be effective in inhibition of the growth of prostate cancer sell lines, in a dose-dependent manner through cell cycle arrest and apoptosis induction(34) specially in LNCaP cells and several androgen-independent PCa cell, through suppression of  prostate cancer growth and androgen receptor(AR) signaling.(35) or through induction of  G1 arrest via activation of p53(tumor antigen) signaling and inhibition of AR in LNCaP cells(36).

13. Ginkgo biloba
Ginkgo biloba is oldest living tree species, genus Ginkgo, belonging to the family Ginkgoaceae, native to China, from temperate zone to subtropical zone and some parts of north America. It has been used in traditional herbal medicine in treating impotence, memory loss,respiratory diseases, circulatory disorders and deafness as well as preventing drunkenness, and bedwetting.
Ginkgetin, isolated from leaves of Ginkgo biloba L, inhibited PC-3 cells in a concentration-dependent manner, through significantly increased the sub-G1(detection of cumulative apoptosis)  DNA contents of cell cycle by activated caspase-3 (mechanisms of apoptosis) and weakened  the expression of survival genes such as Bcl-2, Bcl-xL,(family of regulator proteins that regulate cell death) Survivin (baculoviral inhibitor), and Cyclin D1(regulating cell cycle progression) at protein and mRNA levels(37). Unfortunately, Some reseachers suggested that there were no associations for use of  ginkgo biloba in reduced risk of prostate cabcer(38)(39)

14. Licorice (Glycyrrhiza Glabra)
Licorice (Glycyrrhiza Glabra) also known as sweetwood, is the genus Glycyrrhiza, belonging to the family Fabaceae, native to the Mediterranean and certain areas of Asia. The herb has been used in traditional medicine to treat skin diseases, coughs, constipation, bronchitis, inflammation.
Licochalcone-A, isolated from licorice, induced modest level of apoptosis of androgen-independent PC-3 prostate cancer cells through the cell cycle progression arresting cells in G2/M, accompanied by suppression of cyclin B1 and cdc2(cell division cycle 2)(40). Isoangustone A (IAA) in licorice,  attenuated the growth of prostate cancer cell cultures and xenograft tumors attributed to inhibition of the G1/S phase cell cycle transition and the accumulation of p27(cell cycle inhibitor)(41). Other chemical compound such as Glycyrrhetinic acid found in licorice, in the experiment of prostate cancer cell line DU-145, inhibited proliferation and growth of these cells by inducing apoptosis, through down regulated expression of NF-κB (p65). (42).

15. Peppermint
Peppermint is a hybrid mint with small purple or white flowers and downy leaves, in the genus Mentha, belonging to the family Lamiaceae, native to  Europe. The herb has been used in folk medicine as analgesic, antiseptic, antispasmodic, decongestant, agent and to relieve gas, nausea, and stomach pain due to an irritable bowel, intestinal cramps, or indigestion, infecttion, etc.
Essential oils of peppermint exerted its cytotoxic effect against of  prostate cancer (LNCaP) cell lines(43). Menthol, a naturally isolated from peppermint oil, induced cell death in PC-3 cells independent to Ca(2+) influx pathways(44). When combined with 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], the most active form of vitamin D(3), menthol increased an anti-proliferation activity of 1alpha,25(OH)(2)D(3) in LNCaP prostate cancer cells, through evoking the increase in [Ca(2+)](45).

16. Wolfberry
Wolfberry is the common name for the fruit of two very closely related species, the genus of Lycium, belong to family Solanaceae, native to native to southeastern Europe and Asia.
Lycium barbarum polysaccharides (LBPs) in dose and time-dependently inhibited the growth of both PC-3 and DU-145 cells through exhibiting  the breakage of DNA strands of PC-3 and DU-145 cells and induced apoptosis(46). Extract from Lycium barbarum. showed an inhibited effect against  PC3 cell proliferation(47).

18. Rosemary 
Rosemary is a perennial herb with fragrant, evergreen, needle-like leaves, the genus Rosmarinus, belonging to the family Lamiaceae. Its fresh and dried leaves has been used frequently in traditional Mediterranean cuisine and as flavor foods while barbecuing.
Polyphenols isolated from rosemary, inhibited prostate cancer cell through targeting multiple signaling pathways involved in cell cycle modulation and apoptosis(48). Carnosic acid (CA), a polyphenolic diterpene, isolated from rosemary, induced apoptosis of PC-3 cells, by activation of PP2A(play critical roles in cell cycle and apoptosis) through modulation of Akt/IKK/NF-κB pathway(49).

Taking altogether, The above herbs have shown effectively in reduced risk and treatments of prostate cancer, through induced apoptosis, exhibited anti proliferation of prostate cancer cell line in cell cycle arrest, down regulation of pro cell growth pathways, etc.. Please consult with your doctor or related field specialist before applying.

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References
(1) Aloe-emodin suppresses prostate cancer by targeting the mTOR complex 2 by Liu K, Park C, Li S, Lee KW, Liu H, He L, Soung NK, Ahn JS, Bode AM, Dong Z, Kim BY, Dong Z.(PubMed)
(2) Effect of inhibition of aloe-emodin on N-acetyltransferase activity and gene expression in human malignant melanoma cells (A375.S2) by Lin SY, Yang JH, Hsia TC, Lee JH, Chiu TH, Wei YH, Chung JG.(PubMed)
(3) Aloe-emodin suppresses prostate cancer by targeting the mTOR complex 2 by Liu K, Park C, Li S, Lee KW, Liu H, He L, Soung NK, Ahn JS, Bode AM, Dong Z, Kim BY, Dong Z.(PubMed)
(4) Emodin inhibits invasion and migration of prostate and lung cancer cells by downregulating the expression of chemokine receptor CXCR4 by Ok S, Kim SM, Kim C, Nam D, Shim BS, Kim SH, Ahn KS, Choi SH, Ahn KS.(PubMed)
(5) Emodin induces apoptosis in human prostate cancer cell LNCaP by Yu CX, Zhang XQ, Kang LD, Zhang PJ, Chen WW, Liu WW, Liu QW, Zhang JY.(PubMed)
(6) Chemosensitization by emodin, a plant-derived anti-cancer agent: mechanism of action by Sun Y.(PubMed)
(7) Oral administration of naturally occurring chitosan-based nanoformulated green tea polyphenol EGCG effectively inhibits prostate cancer cell growth in a xenograft model by Khan N, Bharali DJ, Adhami VM, Siddiqui IA, Cui H, Shabana SM, Mousa SA, Mukhtar H.(PubMed)
(8) Effect of a prodrug of the green tea polyphenol (-)-epigallocatechin-3-gallate on the growth of androgen-independent prostate cancer in vivo by Lee SC, Chan WK, Lee TW, Lam WH, Wang X, Chan TH, Wong YC.(PubMed)
(9) Epigallocatechin-3-gallate promotes apoptosis and expression of the caspase 9a splice variant in PC3 prostate cancer cells by Hagen RM, Chedea VS, Mintoff CP, Bowler E, Morse HR, Ladomery MR.(PubMed)
(10) Pomegranate extract inhibits the bone metastatic growth of human prostate cancer cells and enhances the in vivo efficacy of docetaxel chemotherapy by Wang Y, Zhang S, Iqbal S, Chen Z, Wang X, Wang YA, Liu D, Bai K, Ritenour C, Kucuk O, Wu D.(PubMed)
(11) Pomegranate Juice Metabolites, Ellagic Acid and Urolithin A, Synergistically Inhibit Androgen-Independent Prostate Cancer Cell Growth via Distinct Effects on Cell Cycle Control and Apoptosis by Vicinanza R, Zhang Y, Henning SM, Heber D.(PubMed)
(12) Specific pomegranate juice components as potential inhibitors of prostate cancer metastasis by Wang L, Ho J, Glackin C, Martins-Green M.(PubMed)
(13) Cytotoxic effect of the pentacyclic oxindole alkaloid mitraphylline isolated from Uncaria tomentosa bark on human Ewing's sarcoma and breast cancer cell lines by García Giménez D, García Prado E, Sáenz Rodríguez T, Fernández Arche A, De la Puerta R.(PubMed)
(14) The antiproliferative effects of Uncaria tomentosa extracts and fractions on the growth of breast cancer cell line by Riva L, Coradini D, Di Fronzo G, De Feo V, De Tommasi N, De Simone F, Pizza C.(PubMed)
(15) Anticancer activity of the Uncaria tomentosa (Willd.) DC. preparations with different oxindole alkaloid composition by Pilarski R, Filip B, Wietrzyk J, Kuraś M, Gulewicz K.(PubMed)
(16) Garlic-derived S-allylmercaptocysteine is a novel in vivo antimetastatic agent for androgen-independent prostate cancer by Howard EW, Ling MT, Chua CW, Cheung HW, Wang X, Wong YC.(PubMed)
(17) Growth suppressing effect of garlic compound diallyl disulfide on prostate cancer cell line (PC-3) in vitro by Arunkumar A, Vijayababu MR, Kanagaraj P, Balasubramanian K, Aruldhas MM, Arunakaran J.(PubMed)
(18) Garlic constituent diallyl trisulfide suppresses x-linked inhibitor of apoptosis protein in prostate cancer cells in culture and in vivo by Kim SH, Bommareddy A, Singh SV.(PubMed)
(19) Herbal infusions; their phenolic profile, antioxidant and anti-inflammatory effects in HT29 and PC3 cells by Kogiannou DA, Kalogeropoulos N, Kefalas P, Polissiou MG, Kaliora AC.(PubMed)
(20)The effect of a novel botanical agent TBS-101 on invasive prostate cancer in animal models by Evans S, Dizeyi N, Abrahamsson PA, Persson J.(PubMed)
(21) Activities of ten essential oils towards Propionibacterium acnes and PC-3, A-549 and MCF-7 cancer cells by Zu Y, Yu H, Liang L, Fu Y, Efferth T, Liu X, Wu N.(PubMed)
(22) Onion and garlic use and human cancer by Galeone C, Pelucchi C, Levi F, Negri E, Franceschi S, Talamini R, Giacosa A, La Vecchia C.(PubMed)
(23) Dietary flavonoid fisetin: a novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management by Adhami VM, Syed DN, Khan N, Mukhtar H.(PubMed)
(24) Effects of quercetin on insulin-like growth factors (IGFs) and their binding protein-3 (IGFBP-3) secretion and induction of apoptosis in human  prostate cancer cells by J. Vijayababu MR, Arunkumar A, Kanagaraj P, Arunakaran (PubMed)
(25) Combinatorial cytotoxic effects of Curcuma longa and Zingiber officinale on the PC-3M prostate cancer cell line by Kurapati KR, Samikkannu T, Kadiyala DB, Zainulabedin SM, Gandhi N, Sathaye SS, Indap MA, Boukli N, Rodriguez JW, Nair MP.(PubMed)
(26) Demethoxycurcumin Modulates Prostate Cancer Cell Proliferation via AMPK-Induced Down-regulation of HSP70 and EGFR by Hung CM, Su YH, Lin HY, Lin JN, Liu LC, Ho CT, Way TD.(PubMed)
(27) Growth factor receptor expression in anal squamous lesions: modifications associated with oncogenic human papillomavirus and human immunodeficiency virus(Human Patholog)
(28) Effects of cyclohexanone analogues of curcumin on growth, apoptosis and NF-κB activity in PC-3 human prostate cancer cells by Wei X, DU ZY, Cui XX, Verano M, Mo RQ, Tang ZK, Conney AH, Zheng X, Zhang K.(PubMed)
(29) Ginsenoside Rg3 attenuates cell migration via inhibition of aquaporin 1 expression in PC-3M prostate cancer cells by Pan XY, Guo H, Han J, Hao F, An Y, Xu Y, Xiaokaiti Y, Pan Y, Li XJ.(PubMed)
(30) Stereospecificity of hydroxyl group at C-20 in antiproliferative action of ginsenoside Rh2 on prostate cancer cells by Liu J, Shimizu K, Yu H, Zhang C, Jin F, Kondo R.(PubMed)
(31) The effect of a novel botanical agent TBS-101 on invasive prostate cancer in animal models by Evans S, Dizeyi N, Abrahamsson PA, Persson J.(PubMed)
(32) Grape seed extract regulates androgen receptor-mediated transcription in prostate cancer cells through potent anti-histone acetyltransferase activity by Park SY, Lee YH, Choi KC, Seong AR, Choi HK, Lee OH, Hwang HJ, Yoon HG.(PubMed)
(32) Procyanidin B2 3,3″-di-O-gallate, a Biologically Active Constituent of Grape Seed Extract, Induces Apoptosis in Human Prostate Cancer Cells Via Targeting NF-κB, Stat3, and AP1 Transcription Factors by Tyagi A, Raina K, Shrestha SP, Miller B, Thompson JA, Wempe MF, Agarwal R, Agarwal C.(PubMed)
(33) NFkappaB-dependent regulation of urokinase plasminogen activator by proanthocyanidin-rich grape seed extract: effect on invasion by prostate cancer cells by Uchino R, Madhyastha R, Madhyastha H, Dhungana S, Nakajima Y, Omura S, Maruyama M.(PubMed)
(34) Bioactive tanshinones in Salvia miltiorrhiza inhibit the growth of prostate cancer cells in vitro and in mice by Gong Y, Li Y, Lu Y, Li L, Abdolmaleky H, Blackburn GL, Zhou JR.(PubMed)
(35) Tanshinones from Chinese medicinal herb Danshen (Salvia miltiorrhiza Bunge) suppress prostate cancer growth and androgen receptor signaling by Zhang Y, Won SH, Jiang C, Lee HJ, Jeong SJ, Lee EO, Zhang J, Ye M, Kim SH, Lü J.(PubMed)
(36) Activation of p53 signaling and inhibition of androgen receptor mediate tanshinone IIA induced G1 arrest in LNCaP prostate cancer cells by Won SH, Lee HJ, Jeong SJ, Lü J, Kim SH.(PubMed)
(37) Ginkgetin induces apoptosis via activation of caspase and inhibition of survival genes in PC-3 prostate cancer cells by You OH, Kim SH, Kim B, Sohn EJ, Lee HJ, Shim BS, Yun M, Kwon BM, Kim SH.(PubMed)
(38) Specialty supplements and prostate cancer risk in the VITamins and Lifestyle (VITAL) cohort by Brasky TM, Kristal AR, Navarro SL, Lampe JW, Peters U, Patterson RE, White E.(PubMed)
(39) Ginkgo biloba and risk of cancer: secondary analysis of the Ginkgo Evaluation of Memory (GEM) Study by Biggs ML, Sorkin BC, Nahin RL, Kuller LH, Fitzpatrick AL.(PubMed)
(40) Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells by Fu Y, Hsieh TC, Guo J, Kunicki J, Lee MY, Darzynkiewicz Z, Wu JM.(PubMed)
(41) CDK2 and mTOR are direct molecular targets of isoangustone A in the suppression of human prostate cancer cell growth by Lee E, Son JE, Byun S, Lee SJ, Kim YA, Liu K, Kim J, Lim SS, Park JH, Dong Z, Lee KW, Lee HJ.(PubMed)
(42) 18α-glycyrrhetinic acid targets prostate cancer cells by down-regulating inflammation-related genes by Shetty AV, Thirugnanam S, Dakshinamoorthy G, Samykutty A, Zheng G, Chen A, Bosland MC, Kajdacsy-Balla A, Gnanasekar M.(PubMed)
(43) Seasonal variation in content, chemical composition and antimicrobial and cytotoxic activities of essential oils from four Mentha species by Hussain AI, Anwar F, Nigam PS, Ashraf M, Gilani AH.(PubMed)
(44) Menthol regulates TRPM8-independent processes in PC-3 prostate cancer cells by Kim SH, Nam JH, Park EJ, Kim BJ, Kim SJ, So I, Jeon JH.(PubMed)
(45) Menthol Enhances an Antiproliferative Activity of 1alpha,25-Dihydroxyvitamin D(3) in LNCaP Cells by Park EJ, Kim SH, Kim BJ, Kim SY, So I, Jeon JH.(PubMed)
(46) Lycium barbarum polysaccharides induce apoptosis in human prostate cancer cells and inhibits prostate cancer growth in a xenograft mouse model of human prostate cancer by Luo Q, Li Z, Yan J, Zhu F, Xu RJ, Cai YZ.(PubMed)
(47) [Extraction and isolation of active component for inhibiting PC3 cell proliferation in vitro from the fruit of Lycium barbarum L].[Article in Chinese] by Liu XL, Sun JY, Li HY, Zhang L, Qian BC.(PubMed)
(48) Polyphenols from the Mediterranean herb rosemary (Rosmarinus officinalis) for prostate cancer. by Petiwala SM, Puthenveetil AG, Johnson JJ.(PubMed)
(49) Carnosic acid modulates Akt/IKK/NF-κB signaling by PP2A and induces intrinsic and extrinsic pathway mediated apoptosis in human prostate carcinoma PC-3 cells by Kar S, Palit S, Ball WB, Das PK.(PubMed)



III. In Vitamins' Points Of View

A. Vitamin A

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, causing 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 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)and Japan-Hawaii Cancer Study, Kuakini Medical Center, showed 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 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 by 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 also 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.

Chinese Secrets To Fatty Liver And Obesity Reversal
Use The Revolutionary Findings To Achieve 
Optimal Health And Loose Weight

Ovarian Cysts And PCOS Elimination
Holistic System In Existence That Will Show You How To
Permanently Eliminate All Types of Ovarian Cysts Within 2 Months 

Back to Researched articles - Points of view of Vitamins, Foods and Herbs
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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)



B. Vitamin B complex

B.1. Vitamin B2

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 be 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).

  Epidemiological studies, linking vitamin B2 in reduced risk of prostate cancer have produced inconsistent results. In prostate 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)
In 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 considered as a marker in targeted diagnosis of prostate cancer and vitamin B2 is 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.

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)



B.2. Vitamin B6
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.

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,



B.3. Vitamin B12
Vitamin B12, also known as cobalamin, a water-soluble vitamin, found abundantly in a variety of foods, such as fish, shellfish, meat, eggs, dairy products, etc. plays an important role in regulating the functions of nervous system and formation of blood.

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.

Epidemiological studies linking levels of plasma of vitamin B12 in reduced risk of prostate cancer have produced inconclusive results, it may be due to single nucleotide polymorphisms in B(12)-related genes (MTR, MTRR, FUT2, TCN2, TCN1, CUBN, and MUT), tTC(involved in many processes in the body, such as protein production, protein transport, and the cycle of cell division), holo-transcobalamin(markers of vitamin B12 deficiency), holo-haptocorrin, folate, and homocysteine(a non-protein α-amino acid and can be recycled into methionine or converted into cysteine with the aid of B-vitamins)(1). Study from the University of Bristol, showed that the increased B12 and holo-haptocorrin concentrations associated to positive correlation with prostate cancer risk(2)(3). But the University of Bergen, in a prospective cohort in Norway (n = 317 000) study,  showed no association between vitamin B12 status and prostate cancer risk(4).
In a clinical trial of dietary supplements and prostate cancer, found that a combination of antioxidants, isoflavones, lycopenes, minerals, plant oestrogens and vitamins, including vitamin B12 significantly decreased PSA levels compared with placebo(5).

Taking altogether, without going into reviews, combination of treatment included vitamin B12 may be associated to reduced risk of prostate cancer. 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.
 
References
(1) The causal roles of vitamin B(12) and transcobalamin in prostate cancer: can Mendelian randomization analysis provide definitive answers by Collin SM, Metcalfe C, Palmer TM, Refsum H, Lewis SJ, Smith GD, Cox A, Davis M, Marsden G, Johnston C, Lane JA, Donovan JL, Neal DE, Hamdy FC, Smith AD, Martin RM.(PubMed)
(2) Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis by Collin SM, Metcalfe C, Refsum H, Lewis SJ, Zuccolo L, Smith GD, Chen L, Harris R, Davis M, Marsden G, Johnston C, Lane JA, Ebbing M, Bønaa KH, Nygård O, Ueland PM, Grau MV, Baron JA, Donovan JL, Neal DE, Hamdy FC, Smith AD, Martin RM(PubMed)
(3) Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study by Hultdin J, Van Guelpen B, Bergh A, Hallmans G, Stattin P.(PubMed)

(4) Serum folate and vitamin B12 concentrations in relation to prostate cancer risk--a Norwegian population-based nested case-control study of 3000 cases and 3000 controls within the JANUS cohort by de Vogel S, Meyer K, Fredriksen Å, Ulvik A, Ueland PM, Nygård O, Vollset SE, Tell GS, Tretli S, Bjørge T.(PubMed)
(5) 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)



C. Vitamin C

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.

Epidemiological 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).


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)



D . Vitamin D

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, epidemiologically. 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).  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.


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)



E. Vitamin E

The widespread of prostate cancer, once considered 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 fed 0.1% γ-TmT or a control diet for 16 weeks, observation of 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 accompanied with 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)



F. Vitamin K
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.
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.

Epidemiological studies focused in the synthetic version of vitamin K(Vk3) in reduced risk and treatment of prostate cancer have proven successful in certain extents. In human prostate cancer cells (DU145) implanted mice, administration of C/vitamin K(3) showed to exhibit serum alkaline DNase (DNase I) and acid DNase (DNase II) known as circulating tumour marker accompanied by a decrease in DNA expression of the tumor cells(1). Administration of vitamin C (Vit C), vitamin K3 (Vit K3), or vitamin C:vitamin K3 combinations against a prostate cancer cell line (DU145), suggest that vitamin treatment with individual vitamins affects the cytoskeleton(a series of intercellular proteins that help a cell with shape, support, and movement), the mitochondria, and other membranous components of the cell(2).
Vitamin K4 (VK4) is a synthetic version of vitamin K, inhibited proliferation in PC-3 cells with an IC50 value of about 20.94 microM, through cell cycle arrest at the S phase, disruption of the energy production in the surface of cell membrane, up regulation apoptotic and down regulation of proliferative pathways(3). Alpha-tocopheryl succinate (alpha-TOS), the redox-silent vitamin E analogue used in combination with VK3, showed to induce efficiently cell death that resembles autoschizis(cell death), through cell demise, lipid peroxidation, DNA damage, cytoskeleton alteration, lysosomal-mitochondrial perturbation, and release of cytochrome c without caspase activation(4), In a A prostate carcinoma cell line derived from the transgenic murine prostate cancer model (TRAMP), combination of of ascorbate:menadione (VC + VK(3), induced cell death by autoschizis, included cytokeletal changes conducive to cytoplasmic blebbing, self-excisions, and progressive nuclear alteration, through axidative stress(5). and the Co-administration of the vitamins also enhanced the antitumour activity 5- to 20-fold, with increased cytotoxicity through redox cycling and increased oxidative stress(6). On a human prostate carcinoma cell line (DU145), the co administration also showed to enhance cytotoxicity through increased oxidative stress, subsequent membrane damage, and DNA fragmentation (7). Menaquinones (vitamin K(2) in the study of its association with overall cancer incidence and mortality, showed to
associate with a reduced risk of incident and fatal cancer(8) including prostate cancer(9).

Taking altogether, co administration of synthetic vitamin K3 and other vitamins such as vitamin C is associated to reduced risk and treatment of prostate cancer, though cell cycle arrest, up regulation of 
anti profilerative and down regulation of cancer promoter pathways or increased oxidative stress. Overdoses can induce symptoms of Skin rash,  Diarrhea, Nausea, Vomiting, Anemia, etc. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.

References
(1) In vivo reactivation of DNases in implanted human prostate tumors after administration of a vitamin C/K(3) combination by Taper HS, Jamison JM, Gilloteaux J, Gwin CA, Gordon T, Summers JL(PubMed)
(2) Scanning electron microscopy and transmission electron microscopy aspects of synergistic antitumor activity of vitamin C - vitamin K3 combinations against human prostatic carcinoma cells by Gilloteaux J, Jamison JM, Venugopal M, Giammar D, Summers JL(PubMed)
(3) Vitamin K4 induces tumor cytotoxicity in human prostate carcinoma PC-3 cells via the mitochondria-related apoptotic pathway by Jiang Y, Yang J, Yang C, Meng F, Zhou Y, Yu B, Khan M, Yang H(PubMed)
(4) alpha-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate by Tomasetti M, Strafella E, Staffolani S, Santarelli L, Neuzil J, Guerrieri R(PubMed)
(5) Cell death by autoschizis in TRAMP prostate carcinoma cells as a result of treatment by ascorbate: menadione combination by Gilloteaux J, Jamison JM, Neal DR, Summers JL(PubMed)
(6) Synergistic antitumour activity of vitamins C and K3 against human prostate carcinoma cell lines by Venugopal M, Jamison JM, Gilloteaux J, Koch JA, Summers M, Hoke J, Sowick C, Summers JL.(PubMed)
(7) Flow cytometric and ultrastructural aspects of the synergistic antitumor activity of vitamin C-vitamin K3 combinations against human prostatic carcinoma cells by Jamison JM, Gilloteaux J, Venugopal M, Koch JA, Sowick C, Shah R, Summers JL(PubMed)
(8) Dietary vitamin K intake in relation to cancer incidence and mortality: results from the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg) by Nimptsch K, Rohrmann S, Kaaks R, Linseisen J.(PubMed)
(9) Dietary intake of vitamin K and risk of prostate cancer in the Heidelberg cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg) by Nimptsch K, Rohrmann S, Linseisen J.(PubMed)




Health Researcher and Article Writer. Master in Mathematics and BA in World Literature and Literary criticism. All articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.