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.
Cancer letters. 2016 Sep 26 [Epub ahead of print]
Matthew A Ingersoll, Dannah R Miller, October Martinez, C Brent Wakefield, Kuan-Chan Hsieh, M Vijaya Simha, Chai-Lin Kao, Hui-Ting Chen, Surinder K Batra, Ming-Fong Lin
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., Department of Biological Sciences, Clark Atlanta University, Atlanta, Georgia, United States of America., Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; Section of Urology, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan., Department of Medical and Applied Chemistry, Kaohsiung Medical University Kaohsiung, Taiwan., Department of Medical and Applied Chemistry, Kaohsiung Medical University Kaohsiung, Taiwan; Department of Chemistry, National Sun Yat-sen University, Taiwan., Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Taiwan; Orthopaedic Research Center, Kaohsiung Medical University, Taiwan. Electronic address: ., Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America., Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; Section of Urology, Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska, United States of America; College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America. Electronic address: .