Designed modulation of sex steroid signaling inhibits telomerase activity and proliferation of human prostate cancer cells

• Published in: Toxicology and applied pharmacology 2014-10, Vol.280 (2), p.323-334
• Main Authors: Verma, Vikas, Sharma, Vikas, Singh, Vishal, Sharma, Siddharth, Bishnoi, Ajay Kumar, Chandra, Vishal, Maikhuri, J.P., Dwivedi, Anila, Kumar, Atul, Gupta, Gopal
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Androgen Receptor; ANDROGENS; Aniline Compounds - pharmacology; ANTIGENS; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; CELL CYCLE; Cell Line, Tumor; Cell Proliferation - drug effects; DESIGN; Di-indolyl methane; Drug Design; ENZYME ACTIVITY; Estrogen Receptor; ESTROGENS; GENES; Gynecology. Andrology. Obstetrics; Humans; Indoles - pharmacology; Male; Male genital diseases; Medical sciences; METHANE; Mifepristone; MOLECULES; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); NEOPLASMS; Nephrology. Urinary tract diseases; PATHOGENESIS; PROSTATE; Prostate Cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Raloxifene; RECEPTORS; Receptors, Androgen - drug effects; Receptors, Androgen - physiology; Receptors, Estrogen - drug effects; Receptors, Estrogen - physiology; SEX; Signal Transduction - drug effects; TAMOXIFEN; Telomerase; Telomerase - antagonists & inhibitors; Toxicology; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2014.08.002

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 3.0μM (P