Potential Mechanisms for Inhibition of Breast Cancer by Novel Azaresveratrol Analogs: Implications of Estrogen Receptor, Estrogen Metabolism and Cell Death Pathways
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Abstract
Prolonged exposure to estrogens has been implicated in the development of breast cancers. Steroidal estrogens have been implicated in the initiation and progression of cancer. Estrogens bind to their cognate estrogen receptors which translocate to the nucleus and transcriptionally regulate the expression of downstream genes that lead to cellular proliferation. However, the receptor-mediated pathways do not completely explain how estrogens can initiate cancer in normal breast epithelial cells. Studies suggest that estrogen metabolism in the breast may be the mechanism of cancer initiation. Estrogen metabolism in the breast results in increased oxidative stress and production of genotoxic metabolites that form adducts with DNA, eventually leading to genomic instability and initiation of cancer. Epidemiological and experimental evidence suggests that phytoestrogens, natural compounds of plant origin, can have a chemopreventive effect in estrogen induced breast cancer. Resveratrol, a phytoestrogen found in fruits and nuts, has been shown to possess potent anti-oxidant and anti-cancer activities. Several mechanisms of anti-cancer action and multiple molecular targets of resveratrol have been documented in the literature. Despite its anti-cancer properties, poor specificity and low efficacy have prevented the use of resveratrol in clinical settings. Current approaches to address these problems are to develop synthetic derivatives or analogs of resveratrol such that the potency and specificity are enhanced while limiting toxicity iv to normal cells. As an attempt in this direction, we have synthesized a combinatorial library of azaresveratrol analogs and tested their ability in inhibition of breast cancer cell growth. Of the compounds tested, two analogs, namely, HPIMBD and TIMBD, were shown to have better inhibitory effect on cancer cell proliferation compared to the parent compound resveratrol. The goal of our studies was to determine the potential mechanisms of breast cancer inhibition by resveratrol analogs HPIMBD and TIMBD. We also aim at determining the effect of a combination of these analogs with tamoxifen, a known drug approved for inhibition and prevention of breast cancer. Several breast epithelial and breast cancer cell lines were used to perform mechanistic studies. The key findings of our studies presented in the following thesis indicate that a) resveratrol analogs differentially alter the expressions of two main subtypes of estrogen receptors (ERs) α and β and their downstream genes affecting cellular proliferation, b) resveratrol analogs differentially modulate the expressions of estrogen metabolizing cytochrome P450 (CYP) enzymes CYP1A1 and CYP1B1 and aryl hydrocarbon receptor (AhR) affecting estrogen metabolism in cancer and normal breast epithelial cells and c) a combination of resveratrol analogs with tamoxifen has a synergistic inhibitory effect on the growth of breast cancer cells and induction of early autophagy, late apoptosis and inhibition of ERα expression are the possible mechanisms of synergy of this combination. We thus conclude in this study that azaresveratrol analogs HPIMBD and TIMBD are better than resveratrol in inhibiting the proliferation of breast cancer cells and modulation of ERs, estrogen metabolizing enzymes and induction of autophagy and late apoptosis are the possible mechanisms of anti-cancer action. Our preliminary evidence from in vivo nude mice xenograft studies showing tumor regression with HPIMBD and TIMBD treatments, suggests the translational potential of these novel compounds in inhibition of breast cancer.
Table of Contents
Introduction -- Hypothesis and specific aims -- General materials and methods -- Resveratrol analogs differentially regulate the expressions of estrogen receptors -- Resveratrol analogs differentially modulate the expressions of CYP450 enzymes in normal breast epithelial and breast cancer cells -- Resveratrol analogs synergize with tamoxifen in inhibiting the proliferation of breast cancer cells -- Resveratrol analog TIMBD inhibits tumor development in vivo in xenograft mouse model -- Conclusions and future directions
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Ph.D.