Chemopreventive Phytochemicals

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

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Estradiol
Growth factors
MAPK
P
P
P
P
P
DBD
AF-2
AF-1
AH
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Regulation of ER activity by coactivators and
corepressors
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Estrogen Signaling
Hall et al. 2001. J. Biol. Chem., 276 36869-36872
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ER effects on different cell types
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Estrogens can activate growth factor receptor
signaling
Levin ER. Mol.Endocrinol. 200317309-17
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Non-Genomic Effects of Estradiol
Belcher Zsarnovszky, 2001. J. Pharmacol. Exp.
Therap. 299408-414.
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Estrogen has multiple effects
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Antiestrogens can stop harmful effects of estrogen
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SERMs
(Selective Estrogen Receptor Modulators)
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Phytoestrogens
Aherne and OBrien, 2002. Nutrition 1875-81.
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Phytoestrogens
Benassayag, et al., 2002. J. Chromatogr.B
777233-248.
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Comparison of binding affinities and
transactivation of estrogen and phytoestrogens
Belcher Zsarnovszky, 2001. J. Pharmacol. Exp.
Therap. 299408-414
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Dietary Sources of Phytoestrogens
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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.

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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-ß signaling cascades
• Increases epidermal growth factor (EGF) and EGFR
  levels.

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Genistein
4',5,7-Trihydroxyisoflavone

• 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)

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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 777233-248.
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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.

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Post-menopausal therapy

• In 2002, the Womens 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.

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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. 78593S-609S) .

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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.

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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)

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Red wine phytoestrogensResveratrol, 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.