Abstract 4648: Differential regulation of estrogen metabolizing CYP1A1 and CYP1B1 enzymes by novel resveratrol analogs in breast cancer cells

Abstract

Abstract Evidence from epidemiological and experimental studies suggest an association between diets rich in phytoestrogens and reduced risk of breast cancer. Resveratrol, a bioflavonoid, found naturally in grapes, fruits and nuts, has been shown to be a potent chemopreventive agent in vitro. However, poor bioavailability, rapid metabolism and poor specificity limit its use as the preferred anticancer agent. In an attempt to improve the anticancer properties of resveratrol, we synthesized several analogs of resveratrol with appropriate chemical modifications. Of the compounds that were screened for anticancer activity towards breast cancer cells, two analogs, namely, HPIMBD and TIMBD showed better potency and selectivity in inhibiting the growth of breast cancer cell lines while they did not significantly affect the growth of non-neoplastic breast epithelial cell lines. In this study, we investigated the ability of resveratrol and resveratrol analogs in the regulation of estrogen metabolizing genes, cytochrome P450 (Cyp) 1A1, 1B1 and their upstream regulator AhR in breast cancer and non-neoplastic breast epithelial cells. Non-neoplastic breast epithelial cell line MCF-10A and breast cancer cell lines T47D and MDA-MB-231 were treated with resveratrol, HPIMBD or TIMBD. From cells in culture, mRNA and protein was isolated and expression analyses of CYP1A1, CYP1B1 and AhR carried out by PCR and western blot analyses. Unlike resveratrol, HPIMBD and TIMBD significantly induced the mRNA and protein expression levels of CYP1A1 and AhR while they inhibited that of CYP1B1. Also, HPIMBD and TIMBD induced the expression of CYP1A1 in an AhR-dependent fashion while they inhibited CYP1B1 expression of CYP1B1 by a proteosomal degradation pathway. Cyp1A1 preferentially metabolizes estradiol to 2-hydroxyestradiol and Cyp1B1 to 4-hydroxyestradiol. While, 2-hydroxyestradiol and its methylated product are suggested to be chemo-protective, 4-hydroxyestradiol is regarded as a carcinogenic metabolite of estradiol. Taken together, our findings indicate that novel resveratrol analogs HPIMBD and TIMBD differentially regulate the expressions of CYP1A1 and CYP1B1 in breast cancer cells that may have implications in chemoprevention of breast cancer by these analogs. Note: This abstract was not presented at the meeting. Citation Format: Amruta Mukund Ronghe, Anwesha Chatterjee, Subhash Padhye, Hari K. Bhat. Differential regulation of estrogen metabolizing CYP1A1 and CYP1B1 enzymes by novel resveratrol analogs in breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4648. doi:10.1158/1538-7445.AM2015-4648