Ingersoll Matthew A, Miller Dannah R, Martinez October, Wakefield C Brent, Hsieh Kuan-Chan, Simha M Vijaya, Kao Chai-Lin, Chen Hui-Ting, Batra Surinder K, Lin Ming-Fong
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
Department of Biological Sciences, Clark Atlanta University, Atlanta, GA, USA.
Cancer Lett. 2016 Dec 1;383(1):94-105. doi: 10.1016/j.canlet.2016.09.008. Epub 2016 Sep 26.
Despite recent advances in modern medicine, castration-resistant prostate cancer remains an incurable disease. Subpopulations of prostate cancer cells develop castration-resistance by obtaining the complete steroidogenic ability to synthesize androgens from cholesterol. Statin derivatives, such as simvastatin, inhibit cholesterol biosynthesis and may reduce prostate cancer incidence as well as progression to advanced, metastatic phenotype. In this study, we demonstrate novel simvastatin-related molecules SVA, AM1, and AM2 suppress the tumorigenicity of prostate cancer cell lines including androgen receptor-positive LNCaP C-81 and VCaP as well as androgen receptor-negative PC-3 and DU145. This is achieved through inhibition of cell proliferation, colony formation, and migration as well as induction of S-phase cell-cycle arrest and apoptosis. While the compounds effectively block androgen receptor signaling, their mechanism of inhibition also includes suppression of the AKT pathway, in part, through disruption of the plasma membrane. SVA also possess an added effect on cell growth inhibition when combined with docetaxel. In summary, of the compounds studied, SVA is the most potent inhibitor of prostate cancer cell tumorigenicity, demonstrating its potential as a promising therapeutic agent for castration-resistant prostate cancer.
尽管现代医学最近取得了进展，但去势抵抗性前列腺癌仍然是一种无法治愈的疾病。前列腺癌细胞亚群通过获得从胆固醇合成雄激素的完整类固醇生成能力而产生去势抵抗。他汀类衍生物，如辛伐他汀，可抑制胆固醇生物合成，并可能降低前列腺癌的发病率以及进展为晚期转移表型的可能性。在本研究中，我们证明了新型辛伐他汀相关分子SVA、AM1和AM2可抑制前列腺癌细胞系的致瘤性，包括雄激素受体阳性的LNCaP C-81和VCaP以及雄激素受体阴性的PC-3和DU145。这是通过抑制细胞增殖、集落形成和迁移以及诱导S期细胞周期停滞和凋亡来实现的。虽然这些化合物有效地阻断了雄激素受体信号传导，但其抑制机制还包括部分通过破坏质膜来抑制AKT途径。SVA与多西他赛联合使用时对细胞生长抑制也有附加作用。总之，在所研究的化合物中，SVA是前列腺癌细胞致瘤性最有效的抑制剂，证明了其作为去势抵抗性前列腺癌有前景的治疗药物的潜力。
