Ovarian Cancer in Foods Points of View

Kyle J. Norton (Draft Article)

Ovarian cancer is defined as a condition of  abnormal ovarian cells growth of ovarian cells,  It is one of most common cancer in US, according to the statistics adapted from the American Cancer Society's publication, Cancer Facts & Figures 2010, an estimated 21,880 women in the United States will be diagnosed with ovarian cancer and 13,850 deaths.
Depending to the stage and grade of the cancer, chemotherapy such as cisplatin, carboplatin, paclitaxel, liposomal doxorubicin may be necessary to prevent the spread and recurrence of the cancer. Epidemiological studies focusing in vegetables and fruits in reduced risk and treatment of ovarian cancer have not been conclusive(a)(b)(c)(d), some foods have showed to inhibit the progression of cancer with little or no side effects.

1. Cruciferous vegetables Cruciferous vegetables are the group of  vegetables belonging to the family Brassicaceae, including cauliflower, cabbage, cress, bok choy, broccoli etc. A meta-analysis of observational studies in reviews of a total of 4,306 cases in 375,562 controls in 11 independent studies indicated a positive effect of consumption of Cruciferous vegetables in a reduced risk of ovarian cancer in case-control studies(1). Isothiocyanates, antioxidants and chemical constituent in cruciferous vegetable, inhibit the cell viability of human ovarian cancer cells, through improved antioxidant status(2). sulforaphane, SFN the active compound in  Isothiocyanates, inhibited the human ovarian cancer cell lines through down-regulate Bcl-2 (a gene involved in anti-apoptosis) protein levels in both cell types and up- regulate the cleaved poly(ADP-ribose) polymerase (PARP) after 6 days of treatment(3). In  cell lines MDAH 2774 and SkOV-3 with an IC50, SFN exhibited the suppression of growth in a a dose-dependent manner by reduced cell migration and increased apoptotic cell death(4).

2. Garlic
Garlic is a natural superfood healer for its natural antibiotic with antiviral, antifungal, anticoagulant and antiseptic properties. Allium vegetables have been found in many studies to have an inverse association between the frequency of use of and the risk of several common cancers(5). In Human epithelial ovarian cancer cell line A2780, S-allylcysteine (SAC), , an antioxidant and chemical compound extracted from garlic, SAC  induced apoptosis through G1/S phase arrest by decreased the proliferative expression and increased expression of active of pro apoptosis(6). In human ovarian cancer cell lines, SAC and SAMC induced apoptosis through activation of E-cadherin(7).

3. 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. 6-shogaol, achmeical constituent isolated from ginger showed to inhibited cell growth and modulated secretion of angiogenic factors in ovarian cancer cells, through activation of NF-kappaB and and production of VEGF(stimulation of vasculogenesis and angiogenesis) and IL-8(Interleukin 8, a chemokine of the immune system)(8). In human A549, SK-OV-3, SK-MEL-2, HCT15 tumor cells and the transgenic mouse ovarian cancer cell lines, 6-shogaol exhibited the most potent cytotoxicity against cell proliferation(9).

4. Curcumin
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 trditional medicine as anti-oxidant, hypoglycemic, colorant, antiseptic, wound healing agent, and to treat flatulence, bloating, and appetite loss, ulcers, eczema, inflammations, etc.
Curcumin, a major chemical compound found in turmeric, inhibited the proliferation of both cisplatin-resistant (CR) and sensitive (CS) human ovarian cancer cells through cell cycle arrest, by enhancing the p53 phosphorylation and apoptosis through the activation of caspase-3 followed by PARP degradation(10). E24, a novel curcumin analog, in platinum-sensitive (IGROV1) and platinum-resistant (SK-OV-3) human ovarian cancer cells, in  time- and dose-dependently suppressed the growth of both cell lines and synergized with cisplatin to induce apoptosis(11). The Dalhousie University study also showed a positive effect of curcumin in inhibition of ovarian cancer cell lines independently to p53 but involves p38 MAPK activation, ablation of prosurvival Akt signaling(role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration), and reduced expression of the antiapoptotic proteins Bcl-2 and surviving((baculoviral inhibitor)(12).

5. 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.
In the study conduced by Brigham and Women's Hospital, lycopene found abundantly in tomato iintake is inversely associated to risk of ovarian cancer, predominantly in premenopausal women(13). and the Loma Linda University study also showed a significantly reduced risk of all ovarian cancer with higher tomato consumption in comparing intakes > or = five times/week versus never to < 1 time/week(14). But the reviews from FDA's  of the scientific data for tomato and/or lycopene intake with respect to risk reduction for certain forms of cancer, found very limited evidence to support an association between tomato consumption and reduced risks of prostate, ovarian, gastric, and pancreatic cancers(15).

6. Red wine
Red wine made from anthocyan pigments of the skin of the grape
Resveratrol (trans-3,4',5-trihydroxystilbene; RES), a phytoestrogen, exists in grape skin and red wine showed to inhibited on estrogen-dependent ovarian cancer cells  proliferation, through cell cycle arrest at the G1 phase and increased the expression of p21(16). Other researchers suggested that a diet mixed with a dose of 100 mg resveratrol/kg body weight/day for 28 days exhibited effectively in suppressing the in vitro cellular invasion of NuTu-19 ovarian cancer cells(17). The University of Michigan study indicated the effectiveness of  Resveratrol (3,5,4-trihydroxystilbene) in inhibited growth and induced death in a panel of five human ovarian carcinoma cell lines, through association with mitochondrial release of cytochrome c, formation of the apoptosome complex, and caspase activation(18).

7. Organic soybean
Soybean is genus Glycine, the family Fabaceae, one of the legumes that contains twice as much protein per acre as any other major vegetable or grain crop, native to Southeast Asia. Now, it is grown worldwide with suitable climate for commercial profit and a healthy foods.
Genistein(7-difluoromethoxyl-5,4'-di-n-octyl ), as a major isoflavonoid isolated from dietary soybean, inhibited ovarian cancer cell growth and migration, through down-regulated miR-27a expression and significantly increased expression of Sprouty2, a putative miR-27a target gene(19). On bisphenol A (BPA) or 17β-estradiol (E2)-induced cell growth and gene alterations of BG-1 ovarian cancer cells expressing estrogen receptors (ERs), GEN(Glycine) effectively suppressed BG-1 cell proliferation promoted by E2 or BPA throuh inhibiting cell cycle progression and decreased the expression of cyclin D1, a factor responsible for the G1/S cell cycle transition(20). The First Affiliated Hospital of Guangzhou Medical college, the derivative 7-difluoromethoxyl-5,4'-di-n-octylgenistein (DFOG), a novel synthetic genistein, was more potent by exerting strongest activity against CoC1 and SKOV3 cells through cell cycle arrest in the G2/M phase and exhibited apoptotic cell death with concomitant attenuation of Forkhead box protein M1 (FoxM1)(a transcriptional activator involved in cell proliferation.)(21).

8. Olive oil
Olive is belongs to the family Oleaceae, native to the coastal areas of the eastern Mediterranean Basin and south end of the Caspian Sea. Its fruit, is also called the olive and the source of olive oil.
Accumulations of evidence suggested that Olive oil, an integral ingredient of the "Mediterranean diet" may play an important role  in lowering the risk of several types of cancer, including ovarian cancer, through suppressesion of HER2 at the transcriptional level by up-regulating the expression of the Ets protein PEA3 -a DNA-binding protein that specifically blocks HER2 promoter activity- in ovarian cancer cell lines(22). Data from a multicentre case-control study conducted between 1992 and 1999 in Italy, indicated a protective effect of olive oil against ovarian cancer in this Italian population(23). Oleic acid, the main olive oil's monounsaturated fatty acid, showed to suppress the overexpression of HER2 (erbB-2), a well know nutation gene in expression of invasive progression and metastasis in several human cancers, including ovarian cancer(24). Recent study conducted in China also reported that green tea consumption reduced risk of ovarian cancer and increased survival post diagnosis(26).

9. 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. 
"Green tea consumption suggested to enhance the survival of epithelial ovarian cancer", the cohort comprised 254 patients recruited during 1999-2000 with histopathologically confirmed epithelial ovarian cancer and followed up for a minimum of 3 years said, out of 254, 81 (77.9%) of 104 tea-drinkers who survived to the time of interview, compared to only 67 women (47.9%) still alive among the 140 non-drinkers(27). Epigallocatechin‑3‑gallate, phytochemical found in green tea EGCG significantly inhibited the proliferation of OVCAR‑3 cells in a time‑ and concentration‑dependent manner, through increased expression of the activity of p38/MAPK( control of stemness of glioma-initiating cells) and downregulation of the protein expression of MMP2(usually seen in invasive and highly tumorigenic cancers)(28). The study of combination of Epigallocatechin gallate and sulforaphane against paclitaxel-resistant ovarian cancer cells, showed to induced apoptosis of paclitaxel-resistant ovarian cancer cell lines through down-regulating of hTERT(Telomerase reverse transcriptase allows senescent cells that would otherwise become postmitotic and undergo apoptosis) and Bcl-2 and promote DNA damage response(29).


10. Rice bran
Rice bran contains layer between the inner white rice grain and the outer hull. Phytic acid (PA) isolated rice bran induced marked growth inhibition in ovary, with 50% growth inhibition concentration (IC50)(30).In methanolic extracts from Njavara rice bran, showed to exhibit its anti-proliferative property in C6 glioma cells, possibly through superior antioxidant activity as evidenced by scavenging of free radicals including DPPH and NO(31).

12. 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 Lauraceae.
Omega-6 polyunsaturated (n-6) fatty acids found in avocado inhibited the proliferation of ovarian cancer cell(32).

13. Fatty Fish
Fatty fish containing a large amounts of omega-3 fatty acids may be associated to reduced risk of ovarian cancer. High fish intake may be associated with a significantly reduced risk in the 2 case-control studies(33). The Southern Illinois University Carbondale, in hen study indicated that 175 and 700 mg/kg fish oil reduced proliferation and 700 mg/kg increased apoptosis in hen ovaries. may be an effective approach in preventing ovarian carcinogenesis(34).   

14. 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. Omega-3 fatty acids (OM-3FAs) found in flaxseed, showed statistically significant inhibitory effect under the influence of OM-3FAs was detected in all four cell lines, (SKOV-3 [p53 null], TOV-21G [wt p53] and OVCAR-3 [mutant p53]) and one immortalized ovarian surface epithelial cell line (IOSE-29)(35). In hens study, flaxseed mediated reduction in the severity of ovarian cancer, correlated to the reduction in PGE2 in the ovaries of flaxseed-fed hens(36). The Southern Illinois University study also indicated the effective of long term flaxseed enriched diet in decreased ovarian cancer incidence and prostaglandin E₂in hens(37).

Taking altogether, without going into reviews, the list above have found effectively in reduced risk and treatment of ovarian cancer, but further studies with large example size and multi centers are necessary to identify the principle ingredients to validate the their effectiveness. As always, All articles written by Kyle J. Norton are for information & education only, please consult your Doctor & Related field specialist before applying.
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References
(a) Fruit and vegetable consumption and risk of epithelial ovarian cancer: the European Prospective Investigation into Cancer and Nutrition by Schulz M¹, Lahmann PH, Boeing H, Hoffmann K, Allen N, Key TJ, Bingham S, Wirfält E, Berglund G, Lundin E, Hallmans G, Lukanova A, Martínez Garcia C, González CA, Tormo MJ, Quirós JR, Ardanaz E, Larrañaga N, Lund E, Gram IT, Skeie G, Peeters PH, van Gils CH, Bueno-de-Mesquita HB, Büchner FL, Pasanisi P, Galasso R, Palli D, Tumino R, Vineis P, Trichopoulou A, Kalapothaki V, Trichopoulos D, Chang-Claude J, Linseisen J, Boutron-Ruault MC, Touillaud M, Clavel-Chapelon F, Olsen A, Tjønneland A, Overvad K, Tetsche M, Jenab M, Norat T, Kaaks R, Riboli E.(PubMed)
(b) Fruits and vegetables and ovarian cancer risk in a pooled analysis of 12 cohort studies by Koushik A¹, Hunter DJ, Spiegelman D, Anderson KE, Arslan AA, Beeson WL, van den Brandt PA, Buring JE, Cerhan JR, Colditz GA, Fraser GE, Freudenheim JL, Genkinger JM, Goldbohm RA, Hankinson SE, Koenig KL, Larsson SC, Leitzmann M, McCullough ML, Miller AB, Patel A, Rohan TE, Schatzkin A, Smit E, Willett WC, Wolk A, Zhang SM, Smith-Warner SA(PubMed).
(c) Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk by Riboli E¹, Norat T.(PubMed)
(d) Risk of ovarian carcinoma and consumption of vitamins A, C, and E and specific carotenoids: a prospective analysis by Fairfield KM¹, Hankinson SE, Rosner BA, Hunter DJ, Colditz GA, Willett WC.(PubMed)
(1) Cruciferous vegetables consumption and the risk of ovarian cancer: a meta-analysis of observational studies by Han B, Li X, Yu T(PubMed)
(2) The anti-oxidant properties of isothiocyanates: a review by de Figueiredo SM¹, Filho SA, Nogueira-Machado JA, Caligiorne RB.(PubMed)
(3) Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation by Chen H¹, Landen CN, Li Y, Alvarez RD, Tollefsbol TO(PubMed)
(4) Sulforaphane induces cell cycle arrest by protecting RB-E2F-1 complex in epithelial ovarian cancer cells by Bryant CS¹, Kumar S, Chamala S, Shah J, Pal J, Haider M, Seward S, Qazi AM, Morris R, Semaan A, Shammas MA, Steffes C, Potti RB, Prasad M, Weaver DW, Batchu RB(PubMed).
(5) 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)
(6) S-allylcysteine, a garlic derivative, suppresses proliferation and induces apoptosis in human ovarian cancer cells in vitro by Xu YS¹, Feng JG², Zhang D³, Zhang B⁴, Luo M³, Su D⁵, Lin NM(PubMed)
(7) A novel anticancer effect of garlic derivatives: inhibition of cancer cell invasion through restoration of E-cadherin expression by Chu Q¹, Ling MT, Feng H, Cheung HW, Tsao SW, Wang X, Wong YC.(PubMed)
(8) Cytotoxic components from the dried rhizomes of Zingiber officinale Roscoe by Kim JS¹, Lee SI, Park HW, Yang JH, Shin TY, Kim YC, Baek NI, Kim SH, Choi SU, Kwon BM, Leem KH, Jung MY, Kim DK.(PubMed)
(9) Cytotoxic components from the dried rhizomes of Zingiber officinale Roscoe by Kim JS¹, Lee SI, Park HW, Yang JH, Shin TY, Kim YC, Baek NI, Kim SH, Choi SU, Kwon BM, Leem KH, Jung MY, Kim DK.(PubMed)
(10) Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK by Weir NM¹, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, Tridandapani S, Anant S, Kuppusamy P.(PubMed)
(11) Multiple anticancer activities of EF24, a novel curcumin analog, on human ovarian carcinoma cells by Tan X¹, Sidell N, Mancini A, Huang RP, Shenming Wang, Horowitz IR, Liotta DC, Taylor RN, Wieser F.(PubMed)
(12) Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling by Watson JL¹, Greenshields A, Hill R, Hilchie A, Lee PW, Giacomantonio CA, Hoskin DW.(PubMed)
(13) Carotenoids, antioxidants and ovarian cancer risk in pre- and postmenopausal women by Cramer DW¹, Kuper H, Harlow BL, Titus-Ernstoff L.(PubMed)
(14) Dietary risk factors for ovarian cancer: the Adventist Health Study (United States) by Kiani F¹, Knutsen S, Singh P, Ursin G, Fraser G.(PubMed)
(15) The U.S. Food and Drug Administration's evidence-based review for qualified health claims: tomatoes, lycopene, and cancer by Kavanaugh CJ¹, Trumbo PR, Ellwood KC(PubMed)
(16) Induced growth of BG-1 ovarian cancer cells by 17β-estradiol or various endocrine disrupting chemicals was reversed by resveratrol via downregulation of cell cycle progression by Kang NH¹, Hwang KA, Kim TH, Hyun SH, Jeung EB, Choi KC.(PubMed)
(17) Resveratrol exerts differential effects in vitro and in vivo against ovarian cancer cells by Stakleff KS¹, Sloan T, Blanco D, Marcanthony S, Booth TD, Bishayee A.(PubMed)
(18) Resveratrol-induced autophagocytosis in ovarian cancer cells by Opipari AW Jr¹, Tan L, Boitano AE, Sorenson DR, Aurora A, Liu JR.(PubMed)
(19) Oncogenic MicroRNA-27a is a target for genistein in ovarian cancer cells by Xu L¹, Xiang J, Shen J, Zou X, Zhai S, Yin Y, Li P, Wang X, Sun Q.(PubMed)
(20) Genistein, a soy phytoestrogen, prevents the growth of BG-1 ovarian cancer cells induced by 17β-estradiol or bisphenol A via the inhibition of cell cycle progression by Hwang KA¹, Kang NH, Yi BR, Lee HR, Park MA, Choi KC.(PubMed)
(21) Apoptosis induced by 7-difluoromethoxyl-5,4'-di-n-octyl genistein via the inactivation of FoxM1 in ovarian cancer cells by Ning Y¹, Li Q, Xiang H, Liu F, Cao J.(PubMed)
(22) Mediterranean diet, olive oil and cancer by Colomer R¹, Menéndez JA.(PubMed)
(23) Olive oil, seed oils and other added fats in relation to ovarian cancer (Italy) by Bosetti C¹, Negri E, Franceschi S, Talamini R, Montella M, Conti E, Lagiou P, Parazzini F, La Vecchia C.(PubMed)
(24) Mediterranean dietary traditions for the molecular treatment of human cancer: anti-oncogenic actions of the main olive oil's monounsaturated fatty acid oleic acid (18:1n-9) by Menendez JA¹, Lupu R.(PubMed).
(25) Green tea consumption enhances survival of epithelial ovarian cancer by Zhang M¹, Lee AH, Binns CW, Xie X.(PubMed)
(26) Possible role for green tea in ovarian cancer prevention by Lee AH¹, Fraser ML, Binns CW.(PubMed)
(27) Epigallocatechin‑3‑gallate inhibits the proliferation and migration of human ovarian carcinoma cells by modulating p38 kinase and matrix metalloproteinase‑2 by Wang F, Chang Z, Fan Q, Wang L.(PubMed)
(28) Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation by Chen H¹, Landen CN, Li Y, Alvarez RD, Tollefsbol TO.(PubMed)
(29) Epigallocatechin gallate and sulforaphane combination treatment induce apoptosis in paclitaxel-resistant ovarian cancer cells through hTERT and Bcl-2 down-regulation by Chen H¹, Landen CN, Li Y, Alvarez RD, Tollefsbol TO.(PubMed)
(30) Antioxidant and cytotoxicity effect of rice bran phytic acid as an anticancer agent on ovarian, breast and liver cancer cell lines by Norhaizan ME¹, Ng SK, Norashareena MS, Abdah MA.(PubMed)
(31) The antioxidant and antiproliferative activities of methanolic extracts from Njavara rice bran by Rao AS¹, Reddy SG, Babu PP, Reddy AR.(PubMed)
(32) Intake of omega-3 and omega-6 fatty acids and risk of ovarian cancer by Ibiebele TI¹, Nagle CM, Bain CJ, Webb PM.(PubMed)
 (33) Meat, fish, and ovarian cancer risk: Results from 2 Australian case-control studies, a systematic review, and meta-analysis by Kolahdooz F¹, van der Pols JC, Bain CJ, Marks GC, Hughes MC, Whiteman DC, Webb PM; Australian Cancer Study (Ovarian Cancer) and the Australian Ovarian Cancer Study Group.(PubMed)
(34) Anti-inflammatory effects of fish oil in ovaries of laying hens target prostaglandin pathways by Eilati E, Small CC, McGee SR, Kurrey NK, Hales DB¹(PubMed)

(35) The effects of Omega-3 fatty acids on growth regulation of epithelial ovarian cancer cell lines by Sharma A¹, Belna J, Logan J, Espat J, Hurteau JA(PubMed)
(36) Flaxseed enriched diet-mediated reduction in ovarian cancer severity is correlated to the reduction of prostaglandin E(2) in laying hen ovaries by Eilati E¹, Hales K, Zhuge Y, Ansenberger Fricano K, Yu R, van Breemen RB, Hales DB(PubMed)
(37) Long term consumption of flaxseed enriched diet decreased ovarian cancer incidence and prostaglandin E₂in hens by Eilati E¹, Bahr JM, Hales DB.(PubMed)