Prevention of Estrogen Carcinogenesis by Botanicals, SERMs and NO/cGMP Pathway Modulators
Hemachandra, L-P-Madhubhani P.
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The risk of developing hormone dependent cancers in women will increase with long term exposure to estrogens. Estrogen induced cell proliferation in estrogen receptor positive cells (hormonal pathway) and formation of reactive estrogen quinoids mediated by cytochrome P450s (chemical pathway) are believed to contribute to estrogen carcinogenesis. Estrogens (E2) are oxidized to the catechols, 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2) by P450 1A1/1A2 and P450 1B1 respectively. Both catechols are further oxidized to form electrophilic o-quinones which can react with DNA and proteins. Plant extracts have been used worldwide, as dietary supplements for women health particularly for menopausal symptom relief, without strong scientific basis for efficacy. Mounting evidence suggests that botanical dietary supplements also have breast cancer chemopreventive properties. Selective Estrogen Receptor Modulators (SERMs) have been used for chemoprevention and in the treatment of post menopausal osteoporosis. Elevated nitric oxide synthase (NOS) is implicated in the pathophysiology of many tumors and has been linked to tumor status and outcome. The current study focuses on elucidating the influence of extensively utilized botanicals, SERMs and nitric oxide (NO) pathway modulators on oxidative estrogen metabolism and estrogen induced malignant transformation in normal breast epithelial cells (MCF-10A). After treatment of MCF-10A cells with estradiol and botanicals, SERMs and NO modulators; estrogen metabolites were analyzed using LC/MS-MS. In conclusion, there was a significant reduction in oxidative estrogen metabolism with hops (Humulus lupulus), DMA (desmethylarzoxifene), Ral (raloxifene) Baze (bazedoxifene) and the NOS inhibitor L-NAME. Also hops, DMA, Ral and L-NAME could significantly inhibit estrogen induced malignant transformation in MCF-10A cells. Hops modulated oxidative estrogen metabolism via inhibiting the E2 induced expression of CYP450 1B1 and 1A1. These data suggest that the hop extract might posses’ chemopreventive activity through inhibition of genotoxic estrogen quinone formation in addition to its known antioxidant and induction of detoxification enzyme capabilities. Blocking of malignant transformation by SERMs involves upregulation of detoxification enzymes, whereas the mechanism of NO/cGMP modulation does not. The present study suggests that raloxifene and DMA possess chemopreventive activity through inhibition of genotoxic estrogen quinone formation, in addition to their action via estrogen receptors.
Selective Estrogen Receptor Modulators (SERM)
oxidative estrogen metabolism
botanical dietary supplements
Date available in INDIGO2013-06-28T18:05:24Z