A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors

摘要

Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-beta (ER-beta) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)pheny1]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, similar to 25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly. increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-beta and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-alpha antagonist and ER-beta agonist Accordingly, it decreased expression of ER-alpha target PS2 (P < 0.01) and increased expression of ER-13 target TNF-alpha (P < 0.05) genes in PC-3. ER-beta deficient PC-3 (siRNAtransfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphoiylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization. (C) 2015 Elsevier Inc. All rights reserved.