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

作者：Verma Vikas; Sharma Vikas; Singh Vishal; Sharma Siddharth; Bishnoi Ajay Kumar; Chandra Vishal; Maikhuri J P; Dwivedi Anila; Kumar Atul; Gupta Gopal^*

来源：Toxicology and Applied Pharmacology, 2014, 280(2): 323-334.

DOI：10.1016/j.taap.2014.08.002

• Estrogen Receptor
• Androgen Receptor
• Prostate Cancer
• Di-indolyl methane
• Raloxifene
• Mifepristone
• Telomerase

The predominant estrogen-receptor (ER)-beta signaling in normal prostate is countered by increased ER-alpha 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(alpha/beta) 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. D1MA 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-beta, p21 and p27 protein levels in LNCaP cells and exhibited similar to 5 times more selective binding for ER-beta than ER-alpha, in comparison to raloxifene. DIMA exhibited a dose-dependent ER-beta agonism and ER-alpha antagonism in classical gene reporter assay and decreased hTERT (catalytic subunit of telomerase) transcript levels in LNCaP at 3.0 mu M (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-beta mediated telomerase inhibition, by countering actions of ER-alpha and AR. Its unique molecular design can serve as a lead structure for generation of potent agents against endocrine malignancies like the CaP.

• 出版日期2014-10-15