Фітоестрогени: молекулярні механізми дії в онкологічному контексті

О. С. Зотов, О. В. Поступаленко, Р. І. Верещако


Стаття містить аналітичний огляд сучасних публікацій, присвячених можливій ролі фітоестрогенів у патогенезі онкологічних захворювань. З’ясовано, що безпечним є вживання фітоестрогенів з харчовими продуктами, які історично є характерними для даної місцевості та етносу. Фітоестрогенам притаманні складні механізми молекулярної взаємодії з організмом споживача. Вживання фітоестрогенів, навіть у великих кількостях, ще не означає їх дію – важливою є здатність організму до їх засвоєння та/або біоконвертації у активні форми. Фітоестрогени є недостатньо дослідженими, щоб рекомендувати їх широкому колу споживачів з метою профілактики онкологічних захворювань.

Ключові слова

фітоестрогени; злоякісні новоутворення

Повний текст:



Adlercreutz H, Bannwart C, Wahala K et al. Inhibition of human aromatase by mammalian lignans and isoflavonoid phytoestrogens. J. Steroid Biochem. Mol. Biol. 1993, 44, 147–153.

Adlercreutz H. (1990) Western diet and Western diseases: some hormonal and biochemical mechanisms and associations. Scand. J. Clin. Lab. Invest. Suppl., 201, 3–23.

Adlercreutz H. Evolution, nutrition, intestinal microflora, and prevention of cancer: a hypothesis. Proc. Soc. Exp. Biol. Med. 1998, 217, 241–246.

Agarwal R. Cell signaling and regulators of cell cycle as molecular targets for prostate cancer prevention by dietary agents. Biochem. Pharmacol. 2000; 60:1051–1059.

Ahmad N, Adhami VM, Afaq F et al. Resveratrol causes WAF-1/p21- mediated G(1)-phase arrest of cell cycle and induction of apoptosis in human epidermoid carcinoma A431 cells. Clin. Cancer Res. 2001, 7, 1466–1473.

Akiyama T, Ishida J, Nakagawa S et al. Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. 1987; 262(12):5592–559.

Alvero AB, Brown D, Montagna M et al. Phenoxodiol-Topotecan Co-Administration Exhibit Significant Anti-Tumor Activity Without Major Adverse Side Effects. Cancer Biology & Therapy 6:4, e1-e6.

Athar M, Back JH, Kopelovich L et al. Multiple molecular targets of resveratrol: anticarcinogenic mechanisms. Archives of Biochemistry and Biophysics, vol. 486, no. 2, pp. 95–102, 2009.

Atkinson C, Berman S, Humbert O et al. In vitro incubation of human feces with daidzein and antibiotics suggests interindividual differences in the bacteria responsible for equol production. J Nutr. 2004; 134:596–9.

Axelson M, Setchell KDR. The excretion of lignans in rats: evidence for an intestinal bacterial source for this new group of compounds. FEBS Lett. 1981; 123:337–42.

Axelson M, Sjovall J, Gustafsson BE et al. Soya – a dietary source of the non-steroidal oestrogen equol in man and animals. J. Endocrinol. 1984; 102:49–56.

Bhagwat S, Haytowitz DB, Holden JM. USDA Database for the Isoflavone Content of Selected Foods. Release 2.0. U.S. Department of Agriculture, Agricultural Research Service, Nutrient Data Laboratory Home Page:

Bhattacharya S, Darjatmoko SR, Polans AS. Resveratrol modulates the malignant properties of cutaneous melanoma through changes in the activation and attenuation of the antiapoptotic protooncogenic protein Akt/PKB. Melanoma Res. 2011 Jun; 21(3):180–7.

Bishayee A. Cancer prevention and treatment with resveratrol: From rodent studies to clinical trials. Cancer Prev. Res. (Phila Pa) 2009, 2, 409–418.

Bosetti C, Spertini L, Parpinel M et al. Flavonoids and Breast Cancer Risk in Italy. Cancer Epidemiol Biomarkers Prev 2005; 14:805–808.

Boutin JA. Minireview – Tyrosine protein kinase inhibition and cancer. Int. J. Biochem. Cell Biol.1994; 26:1203–1226.

Choueiri TK, Mekhail T, Hutson TE et al. (2006) Phase I trial of phenoxodiol delivered by continuous intravenous infusion in patients with solid cancer. Ann Oncol 17: 860–865.

Chu S, Mamers P, Burger HG et al. 2000. Estrogen receptor isoform gene expression in ovarian stromal and epithelial tumors. Journal of Clinical Endocrinology and Metabolism 85, 1200–1205.

Cimino S, Sortino G, Favilla V et al. Polyphenols: Key Issues Involved in Chemoprevention of Prostate Cancer. Oxidative Medicine and Cellular Longevity. Volume 2012, Article ID632959, 8 pages.

Clerici C, Setchell KDR, Battezzati PM et al. Pasta naturally enriched with isoflavone aglycons from soy germ reduces serum lipids and improves markers of cardiovascular risk. J Nutr. 2007;137:2270–8.

Cormack D, Fadden D. A Review of Pterostilbene Antioxidant Activity and Disease Modification. Oxidative Medicine and Cellular Longevity Volume 2013, Article ID575482, 15 pages.

Cotroneo MS, Wang J, Fritz WA et al. Genistein action in the prepubertal mammary gland in a chemoprevention model. Carcinogenesis 2002, 23, 1467–1474.

Cucciolla V, Borriello A, Oliva A et al. Resveratrol: From basic science to the clinic. Cell Cycle 2007, 6, 2495–2510.

Dang ZC, Audinot V, Papapoulos SE et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) as a molecular target for the soy phytoestrogen genistein. J Biol Chem. 2003; 278(2):962–967.

Davis JN, Kucuk O, Sarkar FH. Genistein inhibits NF-kappa B activation in prostate cancer cells. Nutr Cancer. 1999; 35(2):167–174.

Dechaud H, Ravard C, Claustrat F et al. Xenoestrogen interaction with human sex hormone-binding globulin (hSHBG). Steroids. 1999; 64:328–334.

Food and Drug Administration. Food labeling: health claims; soy protein and coronary heart disease. Food and Drug Administration, HHS. Final rule. Fed. Regist. 1999; 64:57700–57733.

Fortina MG, Ricci G, Foschino R et al. Phenotypic typing, technological properties and safety aspects of Lactococcus garvieae strains from dairy environments. J Appl Microbiol. 2007; 103:445–53.

Franke AA, Custer LJ. High-performance liquid chromatographic assay of isoflavonoids and coumestrol from human urine. J. Chromatogr. B: Biomed. Appl. 1994; 662:47–60.

Frankenfeld CL, Atkinson C, Thomas WK et al. Familial correlations, segregation analysis, and nongenetic correlates of soy isoflavone-metabolizing phenotypes. Exp Biol Med (Maywood). 2004; 229:902–13.

Fulda S, Debatin KM. Resveratrol modulation of signal transduction in apoptosis and cell survival: A mini-review. Cancer Detect. Prev. 2006, 30, 217–223.

Gallo D, Ferrandina G, Giacomelli S et al. Dietary soy modulation of biochemical parameters in DMBA-induced mammary tumors. Cancer Lett. 2002, 186, 43–48.

Gong L, Li Y, Nedeljkovic-Kurepa A et al. Inactivation of NF-kappaB by genistein is mediated via Akt signaling pathway in breast cancer cells. Oncogene. 2003; 22:4702–4709.

Gotoh T, Yamada K, Yin H et al. Chemoprevention of N-nitroso-N-methylurea-induced rat mammary carcinogenesis by soy foods or biochanin A. Jpn J Cancer Res. 1998; 89:137–142.

Herst PM, Davis JR, Neeson P et al. The anti-cancer drug, phenoxodiol, kills primary myeloid and lymphoid leukemic blasts and rapidly proliferating T cells. Haematologica 2009;94:928–934.

Howitz KT, Bitterman KJ, Cohen HY et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003; 425:191–196.

Jefferson WN, Padilla-Banks E, Clark G et al. Assessing estrogenic activity of phytochemicals using transcriptional activation and immature mouse uterotrophic responses. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2002; 777:179–189.

Kang GY, Lee ER, Kim JH et al. (2009) Downregulation of PLK-1 expression in kaempferol-induced apoptosis of MCF-7 cells. Eur. J. Pharmacol., 611, 17–21.

Kao YC, Zhou C, Sherman M et al. (1998) Molecular basis of the inhibition of human aromatase (estrogen synthetase) by flavone and isoflavone phytoestrogens: A site-directed mutagenesis study. Environ.Health Perspect., 106, 85–92.

Klein R, Brown D, Turnley AM. Phenoxodiol protects against Cisplatin induced neurite toxicity in a PC-12 cell model. BMC Neuroscience 2007, 8:61.

Kowalski J, Samojedny A, Paul M et al. (2005) Effect of apigenin, kaempferol and resveratrol on the expression of interleukin-1beta and tumor necrosis factor-alpha genes in J774.2 macrophages. Pharmacol. Rep., 57, 390–394.

Kuiper GGJM, Carlsson B, Grandien K et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors α and β. Endocrinology. 1997; 138: 863–870.

Kuiper GGJM, Lemmen JG, Carlsson B et al. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor β. Endocrinology. 1998; 139: 4252–4263.

Kurahashi N, Iwasaki M, Sasazuki S et al. Soy product and isoflavone consumption in relation to prostate cancer in Japanese men. Cancer Epidemiol Biomarkers Prev. 2007; 16(3):538–545.

Kurzer MS, Xu X. Dietary phytoestrogens. Annu. Rev. Nutr. 1997; 17:353–381.

Kushner PJ, Agard DA, Greene GL et al. Estrogen receptor pathways to AP-1. J. Steroid Biochem. Mol. Biol. 2000; 74:311–317.

Lampe JW. Is equol the key to the efficacy of soy foods? Am J. Clin. Nutr. 2009; 89:1664S–1667S.

Lazennec G, Bresson D, Lucas et al. ER beta inhibits proliferation and invasion of breast cancer cells. Endocrinology 2001, 142, 4120–30.

Lee IH, Cao L, Mostoslavsky R, Lombard DB et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl. Acad. Sci. USA. 2008; 105:3374–3379.

Levi F, Pasche C, Lucchini F et al. Resveratrol and breast cancer risk. Eur. J. Cancer Prev. 2005, 14, 139–142.

Li Y, Wang Z, Kong D et al. Regulation of Akt/FOXO3a/GSK-3beta/AR signaling network by isoflavone in prostate cancer cells. J Biol Chem. 2008 Oct 10; 283(41):27707–16.

Loukovaara M, Carson M, Palotie A et al. Regulation of sex hormone-binding globulin production by isoflavonoids and patterns of isoflavonoid conjugation in HepG2 cell cultures. Steroids 1995, 60, 656–661.

Lund TD, Munson DJ, Haldy ME et al. Equol is a novel anti-androgen that inhibits prostate growth and hormone feedback. Biol Reprod. 2004;70:1188–95.

Luo H, Rankin GO, Juliano N et al. (2012) Kaempferol inhibits VEGF expression and in vitro angiogenesis through a novel ERK-NFkappaB- cMyc-p21 pathway. Food Chem., 130, 321–328.

Luo H, Rankin GO, Liu L et al. (2009) Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in humanovarian cancer cells. Nutr. Cancer, 61, 554–563.

Lurje G, Lenz HJ, FR EG. EGFR signaling and drug discovery. Oncology. 2009; 77:400–410.

Maggi A, Ciana P, Belcredito S et al. Estrogens in the nervous system: mechanisms and nonreproductive functions. Annu. Rev. Physiol. 2004; 66:291–313.

Mahoney S, Arfuso F, Rogers P et al. 2012 Cytotoxic effects of the novel isoflavone, phenoxodiol, on prostate cancer cell lines. J. Biosci. 37 73–84.

Markiewicz L, Garey J, Adlercreutz H et al. In vitro bioassays of non-steroidal phytoestrogens. J. Steroid Biochem. Mol. Biol. 1993; 45:399–405.

Marrian GF, Beall D. The constitution of equol. Biochem J. 1935;29:1586–9.

Marrian GF, Haslewood GA. Equol, a new inactive phenol isolated from the ketohydroxyoestrin fraction of mares’ urine. Biochem J. 1932; 26:1227–32.

Messina M, Nagata C, Wu AH. Estimated Asian adult soy protein and isoflavone intakes. Nutr. Cancer. 2006; 55:1–12.

Messina MJ, Loprinzi CL. Soy for breast cancer survivors: a critical review of the literature. J. Nutr. 2001, 131, 3095S–3108S.

Messina MJ, Persky V, Setchell KD et al. Soy intake and cancer risk: a review of the in vitro and in vivo data. Nutr. Cancer 1994, 21, 113–131.

Micevych P, Dominguez R. Membrane estradiol signaling in the brain. Front. Neuroendocrinol. 2009; 30:315–327.

Mor G, Fu HH, Alvero AB (2006) Phenoxodiol, a novel approach for the treatment of ovarian cancer. Curr Opin Investig Drugs 7: 542–548.

Mortensen A, Kulling SE, Schwartz H et al. Analytical and compositional aspects of isoflavones in food and their biological effects. Mol. Nutr. Food Res. 2009; 53 Suppl.2:S266–S309.

Nilsson A. Demethylation of the plant oestrogen biochanin A in the rat. Nature. 1961;192:358.

Noh JJ, Maskarinec G, Pagano I et al. Mammographic densities and circulating hormones: a cross-sectional study in premenopausal women. Breast 2006, 15, 20–28.

Okura A, Arakawa H, Oka H et al. Effect of genistein on topoisomerase activity and on the growth of [Val 12] Ha-ras-transformed NIH 3T 3 cells. Biochem. Biophys. Res. Commun. 1988; 157:183–189.

Pacholec M, Bleasdale JE, Chrunyk B et al. SRT 2183, SRT 1460, and resveratrol are not direct activators of SIRT 1. J. Biol. Chem. 2010; 285:8340–8351. (1720).

Pelt AM, Rooij DG, Burg B et al. Ontogeny of estrogen receptor-beta expression in rat testis. Endocrinology. 1999; 140:478–483.

Piotrowska E, Jakobkiewicz-Banecka J, Wegrzyn G. Different amounts of isoflavones in various commercially available soy extracts in the light of gene expression-targeted isoflavone therapy. Phytother. Res. 2009.

Rice S, Mason HD, Whitehead SA. Phytoestrogens and their low dose combinations inhibit mRNA expression and activity of aromatase in human granulosa-luteal cells. J Steroid Biochem Mol Biol. 2006; 101(4-5):216–225.

Rissman EF. Roles of oestrogen receptors alpha and beta in behavioural neuroendocrinology: beyond Yin/Yang. J. Neuroendocrinol. 2008; 20:873–879.

Robb EL, Page MM, Wiens BE et al. Molecular mechanisms of oxidative stress resistance induced by resveratrol: specific and progressive induction of MnSOD. Biochem. Biophys. Res. Commun. 2008; 367:406–412.

Rowland IR, Wiseman H, Sanders TA et al. Interindividual variation in metabolism of soy isoflavones and lignans: influence of habitual diet on equol production by the gut microflora. Nutr Cancer. 2000;36:27–32.

Ruiz-Larrea MB, Mohan AR, Paganga G et al. Antioxidant activity of phytoestrogenic isoflavones. Free Radic. Res. 1997; 26:63–70.

Setchell KDR, Clerici C, Lephart ED et al. S-equol, a potent ligand for estrogen receptor beta, is the exclusive enantiomeric form of the soy isoflavone metabolite produced by human intestinal bacterial flora. Am J Clin Nutr. 2005; 81:1072–9.

Setchell KDR, Cole SJ. Variations in isoflavone levels in soy foods and soy protein isolates and issues related to isoflavone databases and food labeling. J Agric Food Chem. 2003;51:4146–55.

Setchell KDR, Faughnan MS, Avades T et al. Comparing the pharmacokinetics of daidzein and genistein with the use of 13C-labeled tracers in premenopausal women. Am J Clin Nutr.2003;77:411–9.

Setchell KDR, Zimmer-Nechemias L, Cai J et al. Isoflavone content of infant formulas and the metabolic fate of these phytoestrogens in early life. Am J Clin Nutr. 1998; 68:S1453–61.

Singh AV, Franke AA, Blackburn GL et al. Soy phytochemicals prevent orthotopic growth and metastasis of bladder cancer in mice by alterations of cancer cell proliferation and apoptosis and tumor angiogenesis. Cancer Res. 2006; 66(3):1851–1858.

Song KB, Atkinson C, Frankenfeld CL et al. Prevalence of daidzein- metabolizing phenotypes differs between Caucasian and Korean American women and girls. J Nutr. 2006; 136:1347–51.

Soyfoods Associations of North America. Soyfood Sales and Trends. 2009.

Streicher W, Luedeke M, Azoitei A et al. (2014) Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARDLBD-Signalling in Human Prostate Cancer Cells. PLoS ONE 9(6): e98566.

Tang SN, Singh C, Nall D et al. The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate (EGCG) to inhibit prostate cancer stem cell characteristics, invasion, migration and epithelial-mesenchymal transition. Journal of Molecular Signaling, vol. 5, article 14, 2010.

This P, Rochefordiere AD, Clough K et al. Phytoestrogens after breast cancer. Endocrine-Related Cancer (2001) 8 129–134.

Thomas P, Dong J. Binding and activation of the seven-transmembrane estrogen receptor GPR30 by environmental estrogens: a potential novel mechanism of endocrine disruption. J. Steroid Biochem. Mol. Biol. 2006; 102:175–179.

UK-Committee-on-Toxicity, Phytoestrogens and Health, Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. London: 2003.

Vedrine N, Mathey J, Morand C et al. One-month exposure to soy isoflavones did not induce the ability to produce equol in postmenopausal women. Eur J Clin Nutr. 2006; 60:1039–45.

Verkasalo PK, Appleby PN, Allen NE et al. Soya intake and plasma concentrations of daidzein and genistein: validity of dietary assessment among eighty British women (Oxford arm of the European Prospective Investigation into Cancer and Nutrition). Br. J. Nutr. 2001; 86:415–421.

Virk-Baker MK, Nagy TR, Barnes S. Role of phytoestrogens in cancer therapy. Planta Med. 2010 August; 76(11): 1132–1142.

Wakai K, Egami I, Kato K et al. Dietary intake and sources of isoflavones among Japanese. Nutr Cancer. 1999; 33:139–45.

Wang TC, Chen IL, Lu PJ et al. Synthesis, antiproliferative, and antiplatelet activities of oxime- and methyloxime-containing flavone and isoflavone derivatives. Bioorg Med Chem. 2005; 13:6045–6053.

Warat M, Szliszka E, Korzonek-Szlacheta I et al. Chrysin, apigenin and acacetin inhibit tumor necrosis factor-related apoptosis-inducing ligand receptor-1 (TRAIL-R1) on activated RAW264.7 macrophages. Int J Mol Sci. 2014 Jun 27; 15(7):11510–22.

Whatmore JL, Swann E, Barraja P et al. Comparative study of isoflavone, quinoxaline and oxindole families of anti-angiogenic agents. Angiogenesis. 2002; 5:45–51.

Wu AH, Ziegler RG, Horn-Ross PL et al. Tofu and risk of breast cancer in Asian-Americans. Cancer Epidemiol Biomarkers Prev. 1996; 5(11):901–906.

Xu W, Liu J, Li C et al. (2008) Kaempferol-7-O-beta-D-glucoside (KG) isolated from Smilax china L. rhizome induces G2/M phase arrest and apoptosis on HeLa cells in a p53-independent manner. Cancer Lett., 264, 229–240.

Yashar CM, Spanos WJ, Taylor DD et al. Potentiation of the radiation effect with genistein in cervical cancer cells. Gynecol Oncol. 2005; 99(1):199–205.

Zava DT, Duwe G 1997 Estrogenic and antiproliferative properties of genistein and other flavonoids in human breast cancer cells in vitro. Nutrition and Cancer 27 31–40.

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