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

• Published in: Toxicology and applied pharmacology Vol. 283; no. 3; pp. 187 - 197
• Main Authors: Kumar, Rajeev, Verma, Vikas, Sharma, Vikas, Jain, Ashish, Singh, Vishal, Sarswat, Amit, Maikhuri, Jagdamba P., Sharma, Vishnu L., Gupta, Gopal
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.03.2015
• Subjects: 60 APPLIED LIFE SCIENCES; ANDROGENS; Animals; Antineoplastic Agents, Hormonal - chemistry; Antineoplastic Agents, Hormonal - pharmacology; APOPTOSIS; Apoptosis - drug effects; Benzopyran; Benzopyrans - chemistry; Benzopyrans - pharmacology; CELL CYCLE; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cercopithecus aethiops; COMPARATIVE EVALUATIONS; COS Cells; Dose-Response Relationship, Drug; Drug Design; ESTRADIOL; Estrogen receptor alpha; Estrogen Receptor alpha - antagonists & inhibitors; Estrogen Receptor alpha - genetics; Estrogen Receptor alpha - metabolism; Estrogen receptor beta; Estrogen Receptor beta - agonists; Estrogen Receptor beta - genetics; Estrogen Receptor beta - metabolism; GENES; Genistein; Humans; LABELLING; Male; MESSENGER-RNA; MODULATION; Molecular Structure; NEOPLASMS; OPTIMIZATION; PHOSPHORYLATION; PROSTATE; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - pathology; RECEPTORS; RNA Interference; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - pharmacology; Signal Transduction - drug effects; Structure-Activity Relationship; TAMOXIFEN; Time Factors; Transfection; Estrogen receptor alpha; Benzopyran; Estrogen receptor beta; Prostate cancer; Genistein; Apoptosis
• DOI: 10.1016/j.taap.2015.01.017
• ISSN: 0041-008X

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-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-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, ~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)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P<0.01) and increased expression of ER-β target TNF-α (P<0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation 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. [Display omitted] •BP with benzopyran core of genistein was identified for ER-β selective action.•BP was 14-times more potent than genistien in targeting prostate cancer cells.•It behaved as a potent ER-β agonist and ER-α antagonist in gene reporter assays.•BP's anti-proliferative action was inhibited significantly in ER-β deficient cells.•BP — a unique lead structure for further optimization.