title: A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors.
abstract: 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.
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Rajeev
authors: R
authors: Kumar
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Vikas
authors: V
authors: Verma
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Vikas
authors: V
authors: Sharma
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Ashish
authors: A
authors: Jain
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Vishal
authors: V
authors: Singh
authors: Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Amit
authors: A
authors: Sarswat
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Jagdamba P
authors: JP
authors: Maikhuri
authors: Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors: Vishnu L
authors: VL
authors: Sharma
authors: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India. Electronic address: g_gupta@cdri.res.in.
authors: Gopal
authors: G
authors: Gupta
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D019556:COS Cells; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D015394:Molecular Structure; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D020845:Selective Estrogen Receptor Modulators / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors; D014162:Transfection
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001578:Benzopyrans; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D020845:Selective Estrogen Receptor Modulators
keywords: Apoptosis; Benzopyran; Estrogen receptor alpha; Estrogen receptor beta; Genistein; Prostate cancer