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Chemopreventive Phytochemicals

Chemopreventive Phytochemicals. ER in cell cycle progression. Myc. ER. Cdc25A. CyclinD1 Cdk4. CyclinE Cdk2. E2F. Rb. DNA pol a Cyclins E,A B-Myb. G1. S. Estrogen Receptor. Estrogen Receptors. http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime. Estrogen Receptors. ER- a

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Chemopreventive Phytochemicals

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  1. Chemopreventive Phytochemicals

  2. ER in cell cycle progression Myc ER Cdc25A CyclinD1 Cdk4 CyclinE Cdk2 E2F Rb DNA pol a Cyclins E,A B-Myb G1 S

  3. Estrogen Receptor

  4. Estrogen Receptors http://www.bio.cmu.edu/Courses/BiochemMols/ER/#ERchime

  5. Estrogen Receptors • ER-a • Uterus, testis, pituitary, ovary, epididymis, and adrenal gland. • ER-b(Kuiper et al. 1996) • brain, kidney, prostrate, ovary, lung, bladder, intestine, and epididymis. • 88% identity with rat ER-b; 47% identity with human ER-a • Membrane localized ER (Pietras and Szego, 1997) • ERa and b differ in C-terminal ligand binding domains and N-terminal transactivation domains. Highest homology in DNA binding domain.

  6. Estradiol Growth factors MAPK P P P P P DBD AF-1 AF-2 AH

  7. Regulation of ER activity by coactivators and corepressors

  8. Estrogen Signaling Hall et al. 2001. J. Biol. Chem., 276: 36869-36872

  9. ER effects on different cell types

  10. Estrogens can activate growth factor receptor signaling Levin ER. Mol.Endocrinol. 2003;17:309-17

  11. Non-Genomic Effects of Estradiol Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414.

  12. Estrogen has multiple effects

  13. Antiestrogens can stop harmful effects of estrogen

  14. SERMs (Selective Estrogen Receptor Modulators)

  15. Phytoestrogens Aherne and O’Brien, 2002. Nutrition 18:75-81.

  16. Phytoestrogens Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.

  17. Comparison of binding affinities and transactivation of estrogen and phytoestrogens Belcher & Zsarnovszky, 2001. J. Pharmacol. Exp. Therap. 299:408-414

  18. Dietary Sources of Phytoestrogens

  19. Pytoestrogens in humans • Phytoestrogens have weaker estrogenic activity compared to circulating estrogens (17-b-estradiol or estrone). • Phytoestrogens can bind sex steroid binding protein (SBP) and a-feroprotein (AFP) and be circulated. • Dietary phytoestrogens are metabolised by intestinal bacteria, absorbed, conjugated in the liver (by sulfotransferases and UDP-glucoronyosyl transferases), circulated in plasma and excreted in urine. • Phytoestrogen levels are higher in fluid collected from breast and prostatic ducts compared with serum or plasma. • Urinary isoflavonoid excretions range from about 0.3-30 mM/day. • Urinary secretions of vegetarians may contain 1000 times higher phytoetsrogens than total urinary steroid estrogens. • Phytoestrogens demonstrate inhibitory effects at 0.5-50mM which are similar to levels in urine.

  20. Soy Phytoestrogens • Genistein, daidzein, coumesterol, and equol bind to and transactivate both ER a and b (0.1-10mM) • Genistetin has a higher affinity for ERb. • Soy PEs effect cell cycle progression, growth, and differentiation. Have antioxidant and anti‑angiogenic activities. • Genistein affects cellular function via inhibition of 17 beta-steroid oxidoreductase (an enzyme necessary for conversion of androgens to E2). • Inhibits aromatase. • Effects cycloxygenase, lipoxygenase, Cholesterol 7a hydroxylase. • Modulates the activity of topoisomerase II. • Modulates enzymes involved in phosphoinositide (PI) turnover. • Modulates TGF-β signaling cascades • Increases epidermal growth factor (EGF) and EGFR levels.

  21. Genistein • Both estrogenic and anti-estrogenic effects • Inhibitor of tyrosine kinases • 20-fold higher binding affinity for ER-b than ER-a(Makela et al. 1999) 4',5,7-Trihydroxyisoflavone

  22. Phytoestrogens in Human Health • Cancer preventive • Post-menopausal supplement • Prevention of osteoporosis • Cardiovascular health • Fertility • Breast enhancement References: Kurzer, 2003. J. Nutr. 133: 1983S-1986S. Benassayag, et al., 2002. J. Chromatogr.B 777:233-248.

  23. Cancer preventive • Benefits to human breast and uterine cancer controversial. • Genistein can be carcinogenic in uterine cancer at neonatal exposure. • Cancer protective in animal studies, especially when exposed during breast development. • Isoflavonoids and lignans stimulate proliferation of ER+ breast cancer cells. • Inhibit cell growth at high concentrations and in ERa (-) breast cancer cells. • Therefore, ER b may have cancer protective effect. • Anti-angiogenic effects of genistein, daidzein, and biochanin A may contribute to antitumor activity. • Anti-oxidants in vitro and in vivo.

  24. Post-menopausal therapy • In 2002, the Women’s Health Initiative (WHI) trial of estrogen/progestin therapy was halted midtrial due to high incidence of breast cancer and cardiovascular disease. • Consumption of 30mg/d soy isoflavones may reduce hot flashes by 30-50%.

  25. Prevention of osteoporosis • Isoflavone intake increases bone mineral density. • Can be useful in preventing post-menopausal osteoporosis. • Diets rich in phytoestrogens can protect long-term bone loss (Setchell & Lydeking-Olsen, 2003. Am. J. Clin. Nutr. 78:593S-609S) .

  26. Cardiovascular health • Average intake of 47g/day soy protein results in 9% decrease in total cholesterol,13% decrease in LDL cholesterol, and a trend towards HDL cholesterol. • Flavanoids decrease platelet aggregation. • Genistein-induced inhibition of growth factor activity can interfere with platelet and thrombin action.

  27. Effects on fertility (premenopausal) • Interferes with menstrual cycle (delay) Reduced LH and FSH and progesterone. • Male rodents exposed to PEs in early life: impaired semen quality, congenital malformations, testicular cancer (coumesterol, delay in mating)

  28. Red wine phytoestrogens:Resveratrol, quercetin, and anthocyanins • Antioxidant, anti‑apoptosis, anti‑inflammatory, anti-cancer, and anti‑invasive. • Reduces Cu-induced LDL oxidation by binding to LDL via a glycosidic ether bond. Increases HDL cholesterol. Inhibits platelet activation. • Ameliorates neuronal damage due to ethanol consumption. Probably via antioxidant effect. Minimizes effects of NOS activity by ehtanol. Inhibits ethanol-induced arachidonic acid release and cycloxygenase activity. • Anti-ageing role? • inhibitory effects on cancer initiation, growth promotion progression and angiogenesis in model systems. • The anti‑proliferative activity of resveratrol is mediated by p38-MAPKs via p53 mediated inhibition. Resveratrol may inhibit apoptosis induced by oxidized lipoproteins through inhibition of NF-kB and AP-1 pathways. • Resveratrol inhibits protein kinase C, Akt, and FAK activities in ER a (+) breast cancer cells.

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