Department of Pharmaceutical Sciences, University of Tennessee Health Science Centre, Memphis, Tennessee.
Department of Biosciences, Jamia Millia Islamia, New Delhi, Delhi, India.
Mol Cancer Ther. 2017 Oct;16(10):2267-2280. doi: 10.1158/1535-7163.MCT-17-0157. Epub 2017 Jun 14.
Ormeloxifene is a clinically approved selective estrogen receptor modulator, which has also shown excellent anticancer activity, thus it can be an ideal repurposing pharmacophore. Herein, we report therapeutic effects of ormeloxifene on prostate cancer and elucidate a novel molecular mechanism of its anticancer activity. Ormeloxifene treatment inhibited epithelial-to-mesenchymal transition (EMT) process as evident by repression of N-cadherin, Slug, Snail, vimentin, MMPs (MMP2 and MMP3), β-catenin/TCF-4 transcriptional activity, and induced the expression of pGSK3β. In molecular docking analysis, ormeloxifene showed proficient docking with β-catenin and GSK3β. In addition, ormeloxifene induced apoptosis, inhibited growth and metastatic potential of prostate cancer cells and arrested cell cycle in G-G phase via modulation of cell-cycle regulatory proteins (inhibition of Mcl-1, cyclin D1, and CDK4 and induction of p21 and p27). In functional assays, ormeloxifene remarkably reduced tumorigenic, migratory, and invasive potential of prostate cancer cells. In addition, ormeloxifene treatment significantly ( < 0.01) regressed the prostate tumor growth in the xenograft mouse model while administered through intraperitoneal route (250 μg/mouse, three times a week). These molecular effects of ormeloxifene were also observed in excised tumor tissues as shown by immunohistochemistry analysis. Our results, for the first time, demonstrate repurposing potential of ormeloxifene as an anticancer drug for the treatment of advanced stage metastatic prostate cancer through a novel molecular mechanism involving β-catenin and EMT pathway. .
奥洛昔芬是一种临床批准的选择性雌激素受体调节剂，它也表现出优异的抗癌活性，因此它可以成为一种理想的重新利用药效团。在此，我们报告奥洛昔芬对前列腺癌的治疗效果，并阐明其抗癌活性的新分子机制。奥洛昔芬治疗抑制上皮间质转化（EMT）过程，表现为 N-钙粘蛋白、Slug、Snail、波形蛋白、MMPs（MMP2 和 MMP3）、β-连环蛋白/TCF-4 转录活性的抑制，以及 pGSK3β 的表达诱导。在分子对接分析中，奥洛昔芬与β-连环蛋白和 GSK3β 显示出良好的对接。此外，奥洛昔芬通过调节细胞周期调节蛋白（抑制 Mcl-1、细胞周期蛋白 D1 和 CDK4 以及诱导 p21 和 p27）诱导前列腺癌细胞凋亡、抑制生长和转移潜能，并将细胞周期阻滞在 G1 期。在功能测定中，奥洛昔芬显著降低前列腺癌细胞的致瘤性、迁移性和侵袭性潜能。此外，奥洛昔芬治疗通过腹腔途径（250μg/只，每周 3 次）显著（<0.01）消退了异种移植小鼠模型中的前列腺肿瘤生长。免疫组化分析显示，奥洛昔芬在切除的肿瘤组织中也观察到了这些分子效应。我们的研究结果首次表明，奥洛昔芬通过一种新的涉及β-连环蛋白和 EMT 通路的分子机制，具有作为治疗晚期转移性前列腺癌的抗癌药物的再利用潜力。
