Prostate cancer in Foods' Points of View

 Kyle J. Norton (Draft article)

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 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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(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)
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(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)

Breast cancer - In foods' Points of View

By Kyle J. Norton (draft article)

The prevalence of breast cancer has been acknowledged in the scientific community worldwide. Breast cancer widespread in women in Southeast Asian as a result of over 2 decades of economic prosperity caused by unhealthy diet is a major concern. The findings for effective treatments are ongoing with some successes, but to discover an effective prevention and treatment with little or no side effects has proven difficulty. According to statistic, one in 8 women will be diagnosed to carry some breast cancer tissues sometimes in their life time. Detections of tumorigenesis through self observation are still the best approach to cure breast cancer in early stage but reduction of the mortality has not been accounted even with extensively modern technology in the field of diagnosis as well as insurance protection in Western world, needless to say of counties which have little. Emerged suggestions of healthy diet with plenty vegetables and fruits(1)(2)(3) with change of life style(4)(5)(6) may be the only choice for women in reducing risk of the diseases.
In fact, certain vegetables(7)(8) and fruits(9)(10) or chemical compounds in them have been found to effect the breast cancer lines, induced apoptosis of breast cells by blocking the energy sources of the pathways, influencing the signal pathways of the proliferation of the cells or suppressing the genes  promoted cancers.
I. Types of vegetables may reduced risk of breast cancer
A. Cruciferous vegetables
Cruciferous vegetables are the group of  vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc.
Isothiocyanate (ITC), one of the major chemical constistuent found in Cruciferous vegetables has been studied extensively over the past three decades with preclinical evidence for the efficacy of various ITCs against cancer in preclinical models. Benzyl isothiocyanate, the derivative of  isothiocyanate showed an effectiveness in influencing carcinogen metabolism and signaling pathways relevant to tumor progression and invasion(11) against MDA-MB-231(breast cancer dell line), human breast cancer xenografts(mutation tissues)(12), suppression of X-linked inhibitor of apoptosis (XIAP) protein expression of cancer cell line MCF-7 by knockdown of the p53(antigens) protein level(13).
In Her-2 positive (a most aggressive case of breast cancer), indole-3-carbinol, a naturally occurring compound found in cruciferous vegetables, used combination with paclitaxel (a mitotic inhibitor) synergistically inhibited growth of Her2/neu human breast cancer cells by arresting cancer cells in the G2(pre-mitotic phase) and M(nuclear division) phase and induction of apoptosis/necrosis(14). I3C used alone also inhibited Her-2breast cancer cell growth in a dose dependent manner as the compound up-regulated Bax(an apoptosis promoter), down-regulated Bcl-2(an apoptosis inhibitor) and, thereby, increased the ratio of Bax to Bcl-2 favoring apoptosis(15).

2. Tomatos
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.
Lycopene, a major carotenoid component of tomato has been known in research community with the property to attenuate the risk of breast cancer. In a time and doses depended, the compound showed an anti-proliferative activity against ER(estrogen receptor)/PR(progesterone receptor) positive MCF-7, HER2-positive SK-BR-3 and triple-negative MDA-MB-468 cell lines by arresting cell cycle at the G₀ /G₁ phase(interphase together - chromosomes replicate in preparation for cell division) at physiologically achievable concentrations(range) found in human plasma(16).  Inhibition of the  ER-positive MCF-7 through the cell cycle progression, ER-negative MDA-MB-231 cells through G1 phase cell cycle-arrest as well as apoptosis(17). There is a report of  a lack of GSTP1 expression in untreated MDA-MB-468. Lycopene treatment not only restored the GSTP1 expression but also
with 2 microM, once per week for 2 weeks induce demethylation of RARbeta2 (tumor suppressor gene) and the HIN-1(a cell growth inhibitor)) genes in the noncancer MCF10A fibrocystic breast cells(18).

3. Figs
N-hexane insoluble fraction (HIF) found in figs may be lesser known for its efficacy in breast cancer cell suppressive activity. The combination of HIF and doxorubicin showed a greater inhibition on cell growth in (Human ductal breast epithelial tumor cell line) T47D cells  and increased the incidence of cells undergoing apoptosis, when compared to exhibited doxorubicin alone(19). The soluble fraction (Ethyl acetate soluble fraction (EASF)) in fig leave was also found to enhance the cytotoxic effect of doxorubicin by changing the inhibition of cell cycle G(2)/M to G(1) phase(20) and Acetone extract of Ficus religosa leaf (FAE)  exerted its efficacy in irreversible inhibition of breast cancer cell growth with moderate toxicity by stimulating the loss of mitochondrial membrane potential in multiple breast cancer cell lines and accelerated cell death through the photosensitizing effect(21).

4. Garlic
Garlic is a natural superfood healer for its natural antibiotic with antiviral, antifungal, anticoagulant and antiseptic properties.
Diallyl trisulfide(DAS), a derived organosulfur compounds (OSCs) suppressed the a ratio of viable cells in the culture of (Human breast cancer cell line) MCF-7 and MCF-12a (a non-tumorigenic epithelial cell line) cells respectively by decreasing the percent of cells in phase G(2)/M and inducing apoptotic cell death as a result of up regulating Bax protein and p53(cellular tumor antigen) protein expression(22). DAS also enhanced the effect of eicosapentaenoic acid, a breast cancer suppressor, and decrese the effect of linoleic acid, a breast cancer enhancer and reduced the side effects caused by anti-cancer agents(23). In the study of a protein fraction from garlic, the fraction was found to be more effective than the augment CD8(+) T-cell infiltration into the tumor site, inhibiting tumor growth more efficiently than garlic extract in enhancing the CD8(+) T-cell infiltration into the tumor site(24).

5. Spinach
Spinach is an edible flowering plant in the genus Spinacia, belonging to the family of Amaranthaceae and native to central and southwestern Asia. It is considered as a healthy plant containing vary vitamins and minerals.
Consuming spinach may be a significantly protective effect on breast cancer among premenopausal women(25). Eating carrots or spinach more than twice weekly, compared with no intake, was associated with an odds ratio of 0.56 (95% confidence interval 0.34-0.91), but does not distinguish among several potential explanations for the protective association observed between intake of carrots and spinach and risk of breast cancer.(26). It is said that included supplementation of A. gangeticus aqueous extract  of red spinach in 5%, 7.5% and 10% in cancer induced rats showed a induction of all tumor marker enzymes especially at 10%.(27).

6. Kelp
Kelps are large seaweeds (algae) growth under shallow in underwater of shallow oceans belonging to the class Phaeophyceae in the order Laminariales, with the thallus is used for food in many cultures. Laminaria, a brown kelp seaweed containg a antibiotic substance, 1-3 beta glucan, was effective in stimulating the host-mediated immune response and was suggested of playing a essential role in preventing  the initiation of breast cancer(28). Japanese seaweed (Laminaria angustata) extracts exerted its antimutagenic effects in certain breast and colon carcinogen(29). L-tryptophana substances isolated from the kelp rhizoid, may play an important role in in the inhibition of cell proliferation as an suggestion of increased tryptophan degradation occurred in women with early-stage breast cancer(30)(31).

7. Chili peppers
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 (trans-8-methyl-N-vanillyl-6-nonenamide), a chemical constituent of chili peppers used in many cultures as anti cancer agent was found to inhibit the growth of ER-positive (MCF-7, T47D, BT-474) and ER-negative (SKBR-3, MDA-MB231) breast cancer cell lines, reducing 50% the size of MDA-MB231 breast cancer tumors(32), induceing cellular apoptosis through a caspase-independent pathway in MCF-7 cells(33). In the comparison of capsaicin and Dohevanil, synthesized from DHA and vanillylamine (precursor to capsaicin) showed the exhibited effects of both vanilloids and dohevanil  in growth inhibition and DNA fragmentation induction in MCF-7 cells, but dohevanil was more potent than capsaicin(34).
 
8. Carrot
Carrot can grow to 3ft tall. It is root vegetable with orange color normally, a sub spices of Daucus carota, belongs to the family Apiaceae, native to Asian and Europe.
Intake of cruciferous vegetable and carrot are inversely associations with risk of estrogen receptor-negative/progesterone receptor-negative breast cancer(35). Wild carrot or Daucus carota L. ssp. carota (Apiacea) oil extract, used in traditional medicine in Lebanon and in different regions throughout the world  was found to inhibit human colon (HT-29, Caco-2) and breast (MCF-7, MDA-MB-231) cancer cell lines, causing significant increase in cell death and decrease in cell proliferation(36).

B. Types of fruit may reduced risk of breast cancer 
1. Blueberry 
Blueberry is a flower plant, belonging to the family Eriaceae and native to Northern America. It can grows from 10 cm to 4 metres tall.
Triple-negative breast cancer TNBC, a cancer does not express the genes for estrogen receptor (ER),  progesterone receptor(PR), and HER2(gene)expression, affecting approximately 15% of all caner cases. Female MDA-MB-231 tumor-bearing mice fed with high fat diet with 5% whole blueberry powder (BB), showed an inhibited TNBC and TNBC-related metastasis by reducing inflammation via specific cytokine-driven pathways with generation of an immune response to reduce tumor growth and metastasis(40). In 17β-estradiol-mediated mammary tumorigenesis,  5% blueberry diet, showed to reduce tumor volume and multiplicity significantly, by down regulation of CYP 1A1(enzymes, able to activate compounds with carcinogenic properties) and ER-α (a  receptor activated by the sex hormone estrogen)genes expression and also favorable modulation of microRNA (mir-18a and mir-34c) levels in gene regulation(41). Other chemical constituents anthocyanin and an anthocyanin-pyruvic acid adduct extract of blueberry were found to inhibited cancer cell proliferation by acting as cell antiinvasive factors and chemoinhibitors(42).

2. 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 and Central America, belonging to the flowering plant family Lauraceous.
It is suggested that avocado-produced toxin persin may contain a positive anti breast cancer effect(43), as persin selectively induces a G2-M cell cycle arrest and cell death through caspase-dependent pathway(44). Others in the study of the same, persin showed a anti breast  cancer effect in both   estrogen receptor (ER) and ER-negative breast cancer cells(45).

3. Strawberry
Strawberries is a genius of Fragaria × ananassa belonging to the family Roseaceae. They have been grown all over the world with suitable climate for commercial profits and for health benefits.
Methanolic extract of strawberry (MESB) fruits showed to induced cytotoxicity in cancer cells, irrespective of origin, in a concentration- and time-dependent manner, in the testing against leukaemia (CEM) and breast cancer (T47D) cell lines through Induction of intrinsic pathway of apoptosis by activating p73 (a tumor suppressor) in breast cancer cells, when tumor suppressor gene p53 was mutated(46). Polyphenols, a major chemical component found in strawberry, as an extract,  induced cytotoxic with doses of approximately 50 microg/ml, causing a 50% reduction in cell survival in both the normal and the tumour lines, including (MCF-7) breast cancer cell lines(47). In other study, freeze-dried fruits of two strawberry cultivars ethanol extract, strongly inhibited CaSki and SiHa cervical cancer cell lines and MCF-7 and T47-D breast cancer cell lines(48).

4. Pomegranate
Pomegranate is a fruit-bearing small tree, genus Punica, belonging to family Lythraceae, native to Iran but has been cultivated in Asian since ancient time.
Pomegranate extracts and genistein were found to exert their anti cancer effect in growth inhibition of cell proliferation and induction of apoptosis in human breast cancer cells(MCF-7) in doses and time depending manner(49) by downregulated HR genes (a ubiquitous cellular pathway that mediates transfer of genetic information) and increased expression of microRNAs (miRNAs), miR-183 (predicted target RAD50) and miR-24 (regulation of gene expression) in enhancing the growth inhibition and apoptosis of MCF-7 breast cancer cell line(50). Pomegranate fruit extracts (PFEs), in dose-dependent inhibited NF-kB-dependent reporter gene responses associated with proliferation, invasion, and motility in aggressive breast cancer phenotypes while decreasing RhoC and RhoA protein expression as these genes are associated with tumor cell invasion and metastasis(51).

6. Grapes 
Resveratrol, a polyphenolic compound known as a good chemopreventive agent for inhibiting carcinogenesis processes that target the regulators of cell function and DNA replication, found abundantly in grapes, berries and peanuts are associated to reduced risk of breast caner. HS-1793, a synthetic version of the compound induced G2/M(DNA damage checkpoint) arrest in the cell cycle progression in both types of cells and involved in cell-cycle arrest and probably in induction of p53(tumor suppressor gene)-dependent apoptosis in MCF-7 cells(52). Catechin (RQC), a polyphenol, was found to be effective in inhibiting mammary tumor growth and metastasis, by reduced Akt(multiple cellular processes0 activity, induced the activation of AMPK(cellular energy), and inhibiting mTOR(mediate cellular responses) signaling in breast cancer cells(53). In Her-2 breast cancer, fox grape seed extract increased the expression of Bax(an apoptosis promoter) and AIF(Apoptosis inducing factor), and decreased total PARP(cellular processes) expression, leading to significant downregulation of Her-2 in MCF-7 cells(54).

7. Pineapple
Pineapple is a species of Ananas Comos, belonging to the family Bromeliaceae and native to southern Brazil and Paraguay. Today it is widely cultivated for commercial uses. Its rich of vitamins and mineral and digesting enzyme bromelin seems to help digestion after a high protein meal. It is a second only to banana as America's most favourite tropical fruit.
Bromelain, a major chemical constituent or  herb used in traditional medicine found in pineapple has exerted its anti-metastasis of breast caner by up regulating the function of c-Jun N-terminal kinase in cell proliferation, differentiation, survival and migration and p38 kinase, in regulation of programmed cell death(56). In GI-101A breast cancer cells, bromelain induced cell death via activation of the apoptosis mechanism, in increased dose-dependent by promoting apoptosis and cytokine processing of caspase-9 and caspase-3 coinciding with elevation of serum CK18 levels(56). In the brMDA-MB-231 mammary carcinoma, oral administration of bromelain increased the reduced bMAK- and MAK-cell activity in cell cycle regulation from 7.8% to 54% (bMAK-cell activity) and from 16% to 47% (MAK-cell activity by stimulating the deficient monocytic cellular cytotoxicity of mammary tumor(57).

8. 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 originated in Central Asia.
In estrogen-dependent MCF-7 and estrogen-independent MDA-MB-231 breast cancer cell lines, apple phytochemical extracts significantly inhibited cell proliferation in a dose-dependent manner and cell cycle modulation(58). In breast carcinoma Mcf-7 and Mcf-7:Her18 cells, peels of apple was, found to be effective in antiproliferation  accompanied by a G0-G1 phase arrest in cell cycle of breast cancer cells by a tumor suppressor protein that suppressed the regulation of cell invasion, metastasis, and angiogenesis(59). Study of apple extracts and quercetin 3-beta-d-glucoside combination, also showed to possess the synergistic effect in MCF-7 cell proliferation(60).

9. Orange
Orange is a species of Citrus Sinensis, belonging to the family Rutaceae and native to the Southeast Asia. Orange is round citrus fruits with finely-textured skins, orange in color and one of most popular fruits in the world.
Polymethoxyflavones (PMFs), a chemical compound found in Sweet orange (Citrus sinensis L.) peel, showed to induce Ca(2+)-mediated apoptosis in human breast cancer cells by induced proapoptotic activity(61). D-limonene, another compound in orange peel oil, in rodent studies, also exhibited its chemotherapeutic activity against mammary, through the induction of tumor cell apoptosis, tumor redifferentiation, and/or suppression of key proteins of cell growth-regulating (62).

C. Others
1.  Black Rice
Black Rice is a type of rice with enriched Anthocyanins. including Indonesian black rice and Thai jasmine black rice. It has been considered as one of nature super foods with vary antioxidants.
Anthocyanins in black rice, with oral administration of AEBR (100 mg/kg/day) to BALB/c nude mice bearing MDA-MB-453 cell xenografts significantly suppressed tumor growth and angiogenesis by suppressing the expression of the physiological process factors MMP-9MMP-2( enzymes involved in the breakdown of extracellular matrix), and uPA(activator) in tumor tissue. Altogether, this study suggests the anticancer effects of AEBR against human breast cancer cells by inducing apoptosis and suppressing angiogenesis(37)(38). Other chemical constituents of species of black glumed’ Njavara (Oryza sativa L.) isolation, namely, flavonolignans, tricin 4'-O-(erythro-β-guaiacylglyceryl) ether (compound 1) and tricin 4'-O-(threo-β-guaiacylglyceryl) ether (compound 2), were also found to exert its effect on  breast cancer cell line MCF-7, causing apoptosis at concentration 40 and 30 μg/ by decreasing protein in the mitochondrial membrane, leading to chromatin condensation(39).

2. 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.
As suggestions, regular green tea intake has been associated with an inverse risk of breast cancer, as  green tea enhanced  the production of Ki-67, a cancer antigen when compare to women who do not.(63). (-)-epigallocatechin gallate, a phytochemical in green tea was found to exert its epigenetic effects by altering the DNA methyltransferase expression in many types of cancer, including breast cancer(64). Catechins, another phytochemical of green tea, inhibited proliferation of breast cancer cells and blocked carcinogenesis in breast cancer propably through the expression of translocation across membranes or for degradation, ribonucleoprotein DNA reduplication, apoptotic cascade, etc.(65). In inflammatory breast cancer, a most aggressive type of breast cancer, green tea polyphenol epigallocatechin-3-gallate (EGCG), showed decreased expression of genes that promote proliferation, migration, invasion, and survival in human breast cancer cell lines, SUM-149 and SUM-190 by reduced lymphangiogenesis-promoting genes(66) and inhibited the cell proliferation at 72 hours, after 10 microM of EGCG treatment. These suggests a possible reactivation of apoptosis, may be through the complexity of the angiogenic switch leading to the modulation of the cell migration processes against triple negative breast cancer cells(67). In human breast cancer MCF-7 cells, selium containg polysaccharides (Se-GTPs) from a new variety of selenium-enriched Ziyang green tea, in dose-dependent, exhibited an effective cell growth inhibition by inducing MCF-7 cancer cells to undergo G2/M(cell cycle) phase arrest and apoptosis by an up-regulation of p53 (tumor antigan) expression(68). Unfortunately, epidemiological data,  on incidence of breast cancer and recurrence of breast cancer, consumption of 5 or more cups of green tea a day showed a non-statistically significant trend towards the prevention of breast cancer development. Evidence indicates that green tea consumption may possibly help prevent breast cancer recurrence in early stage (I and II) cancers(69).

3. Red wine
Red wine, made from the pigments of grape varieties is a wine involved extraction of color, and flavour components from the grape skin.
Red wine phenolics piceatannol and myricetin showed to inhibit the profileration of estrogens hormone-dependent breast cancer cells by binding to the gene expression of estrogen receptor (ER) alpha, which interacts with responsive DNA sequences located within the promoter region of target genes(70). Catechin hydrate (CH), an antioxidant in red wine, induced apotoposis against MCF-7 cells, with the rate of 40.7% and 41.16% in the volume of 150 μg/ml CH in 24 hours, resulting in  apoptotic cells, respectively. Moreover, a 48-hour exposure to 150 μg/ml CH and 300 μg/ml CH resulted in 43.73% and 52.95% apoptotic cells, through its ability to increase the expression of pro-apoptotic genes such as caspase-3, -8, and -9 and TP53(71).

4. Black bean
Black bean is a Small roughly ovoid legumes with glossy black shells, genus Phaseolus, belonging to the family Fabaceae and can bought in most grocery stores all around the year in dried and canned forms. It is believed that black bean was first domesticated growth in South America.
Water-soluble condensed tannins isolated from black beans showed inhibition against breat cancer cell line MCF-7 at 24 microM by suppressed fetal bovine serum (blood fraction remaining after the natural coagulation of blood) stimulated cell migration and the secretion of matrix metalloproteinase-2 (MMP-2 or gelatinase A), matrix metalloproteinase-9 (MMP-9 or gelatinase B)(involved in the breakdown of extracellular matrix), and vascular endothelial growth factor VEGF(165)(regulator of angiogenesis) receptors expression(72). Phytochemical of black bean (Phaseolus vulgaris) seed coats, have potent antioxidant and antiproliferative activities against MCF-7 human breast cancer cells in doses depending manner(73).

5. Fermented soybean
Fermented soybean made from ground soybeans, is an popular ingredient used in cuisines of East and Southeast Asia.
Chungkookjang, a Korean fermented soybean, containing high concentration of isoflavones and peptides showed to inhibit the growth of breast cancer MCF7 cells in decreased dependent on the concentration by activating TGFβ pathway in cellular processes and depressing inflammation(74).
in murine breast adenocarcinoma,  fermented soy product (FSP) showed an effectiveness in tumor containment with smallest tumor volumes. Expressed larger amounts of nitric oxide and IL-1β (regulation of immune and inflammatory responses) and exhibited larger tumor sizes(75).

6. Peanut
Peanuts is belong to the the legume related to the bean family and first cultivated in the in the Chaco region of Paraguay and Bolivia.
Lectin ( (PNA), a chemical constituent of peanut was effective in inhibiting proliferation of human breast cell lines (ZR-75.1 and 734-B)(76) and MCF-7, T 47D, HBL 100, BT 20(77). beta-Sitosterol found in  legumes, oil seeds and unrefined plant oils such as peanut butter, pistachios and sunflower, showed to exhibit the extrinsic apoptotic programmed cell death pathway in human breast MCF-7 and MDA-MB-231(78).

7. Faxseed
Flax seed is native to the region of the eastern Mediterranean to India and also known as common flax or linseed. Flax, an erect annual plant, can grow to 1.2 m tall. The leaves are 20–40 mm long and 3 mm broad.
Study of athymic mice fed with basal diet (control), or 10% FS diet, with or without TRAS (2.5mg/kg) treatment for 5 wk, showed a positive effects in reduced tumor size and increased tumor apoptosis. Dietary FS improved the function of TRAS in increased overall survival(79). In dietary flaxseed lignan or oil combined with tamoxifen showed an enhancing effect in reducing growth of estrogen receptor positive breast tumors (MCF-7) at low circulating estrogen levels by inhibiting cell proliferation, expression of genes, and proteins involved in the ER- and growth factor-mediated signaling pathways(80), with FO greatest effect in increasing apoptosis compared with TAM treatment alone(80). Lignans (a class of phytoestrogens) consumption was associated with a significant reduction in breast cancer risk(81). In estrogen-receptor-positive (MCF-7) and estrogen-receptor-negative (MDA-MB-231) cells, Flaxseed sprouts induced apoptosis and inhibit cancer cell growth by significantly upregulated p53(Anti tumor antigen) mRNA (transmits genetic information from DNA to the cytoplasm and controls certain chemical processes in the cell) in both cell cancer lines(82).

Many hours have been spent, hundred studies have been read, they may be worthless, if this article can not induce some women to change their diet patterns toward plenty vegetables and fruits accompanied with healthy style of living. Vegetables and fruits in the article, indeed, showed a positive effect in inhibiting proliferation  and caused apoptosis in many breast cancer cell lines. But with expansions of GMOs into almost all food sources in production of large scale, approved by FDA and promoted by elective officials for commercial profits with lack of long term studies, organic farming are in the defendant corner waiting for the death sentence in the next super gene of GMOs cross contamination. Will the foods in this article be the same in the future? Will they still exert their anti breast cancer effects?
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