Verma Vikas, Sharma Vikas, Singh Vishal, Sharma Siddharth, Bishnoi Ajay Kumar, Chandra Vishal, Maikhuri J P, Dwivedi Anila, Kumar Atul, Gupta Gopal
Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
Toxicol Appl Pharmacol. 2014 Oct 15;280(2):323-34. doi: 10.1016/j.taap.2014.08.002. Epub 2014 Aug 11.
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.
正常前列腺中占主导地位的雌激素受体（ER）-β信号传导，在前列腺癌（CaP）中会因ER-α信号传导增加而受到对抗，这与雄激素受体（AR）信号传导共同作用导致疾病的发生。然而，CaP治疗大多针对AR信号传导，这种方法最初有效，但最终会导致雄激素抵抗，因此有人提出同时靶向雌激素受体。通过结合已知的抗CaP分子（即通过调节ER（α/β）和/或AR起作用的3,3'-二吲哚甲烷（DIM）、米非司酮、托瑞米芬、他莫昔芬和雷洛昔芬）的药效基团，设计了一系列具有多种性甾体受体调节能力的新型分子。N,N-二乙基-4-((2-(4-甲氧基苯基)-1H-吲哚-3-基)甲基)苯胺（DIMA）被确定为该新系列中最有前景的结构。在体外，DIMA增加了膜联蛋白-V标记、细胞周期停滞和半胱天冬酶-3活性，并降低了LNCaP细胞中AR和前列腺特异性抗原的表达。同时，DIMA增加了LNCaP细胞中ER-β、p21和p27蛋白水平，与雷洛昔芬相比，对ER-β的选择性结合比对ER-α高约5倍。在经典基因报告试验中，DIMA表现出剂量依赖性的ER-β激动作用和ER-α拮抗作用，并在浓度为3.0 μM时降低了LNCaP细胞中hTERT（端粒酶催化亚基）的转录水平（P<0.05）。DIMA还剂量依赖性地降低了前列腺癌细胞中的端粒酶活性。因此得出结论，DIMA作为一种多甾体受体调节剂，通过对抗ER-α和AR的作用，通过ER-β介导的端粒酶抑制作用有效抑制前列腺癌细胞的增殖。其独特的分子设计可作为开发针对CaP等内分泌恶性肿瘤的强效药物的先导结构。
