title: Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells.
abstract: The predominant estrogen-receptor (ER)-β signaling in normal prostate is countered by increased ER-α signaling in prostate cancer (CaP), which in association with androgen-receptor (AR) signaling results in pathogenesis of the disease. However CaP treatments mostly target AR signaling which is initially effective but eventually leads to androgen resistance, hence simultaneous targeting of ERs has been proposed. A novel series of molecules were designed with multiple sex-steroid receptor modulating capabilities by coalescing the pharmacophores of known anti-CaP molecules that act via modulation of ER(α/β) and/or AR, viz. 3,3'diindolylmethane (DIM), mifepristone, toremifene, tamoxifen and raloxifene. N,N-diethyl-4-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl) aniline (DIMA) was identified as the most promising structure of this new series. DIMA increased annexin-V labelling, cell-cycle arrest and caspase-3 activity, and decreased expression of AR and prostate specific antigen in LNCaP cells, in vitro. Concurrently, DIMA increased ER-β, p21 and p27 protein levels in LNCaP cells and exhibited ~5 times more selective binding for ER-β than ER-α, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-β agonism and ER-α antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0 μM (P<0.05). DIMA also dose-dependently decreased telomerase enzyme activity in prostate cancer cells. It is thus concluded that DIMA acts as a multi-steroid receptor modulator and effectively inhibits proliferation of prostate cancer cells through ER-β mediated telomerase inhibition, by countering actions of ER-α and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Verma
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Singh
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Ajay Kumar
authors.initials: AK
authors.lastname: Bishnoi
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Vishal
authors.initials: V
authors.lastname: Chandra
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: J P
authors.initials: JP
authors.lastname: Maikhuri
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Anila
authors.initials: A
authors.lastname: Dwivedi
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
authors.forename: Atul
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India. Electronic address: g_gupta@cdri.res.in.
authors.forename: Gopal
authors.initials: G
authors.lastname: Gupta
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011944:Receptors, Androgen / Q000187:drug effects* / Q000502:physiology; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D019098:Telomerase / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D007211:Indoles; C000594978:N,N-diethyl-4-((2-(4-methoxyphenyl)-1H-indol-3-yl)methyl)aniline; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D019098:Telomerase
keywords: Androgen Receptor; Di-indolyl methane; Estrogen Receptor; Mifepristone; Prostate Cancer; Raloxifene; Telomerase