The HSP90 inhibitor 17-PAG effectively inhibits the proliferation and migration of androgen-independent prostate cancer cells.

Castration-resistant prostate cancer (CRPC) ultimately occurs after a period of treatment with androgen deprivation therapy. Furthermore, CRPC patients can only derive limited survival benefits from traditional cytotoxic drugs. HSP90, which is a molecular chaperone, plays a vital role in client protein processing and maintaining the function of cells. HSP90 is usually overexpressed in prostate cancer tissues, which makes it a potential target for managing prostate cancer. Geldanamycin (GA), which was recognized as the first natural HSP90 inhibitor, has demonstrated potent anti-tumor efficacy in large-scale pre-clinical studies, but its application in the clinic is not permitted due to its liver toxicity and unstable physical properties. In this study, we report a new GA derivative, 17-PAG (17-(propynylamino)-17-demethoxygeldanamycin), which demonstrates highly effective anti-tumor activity against androgen-independent prostate cancer cells. Treating cells with 17-PAG dose-dependently suppressed proliferation, reduced colony formation and induced apoptosis of DU-145/C4-2B cells. Moreover, 17-PAG suppressed the migration and invasion of DU-145/C4-2B cells by regulating epithelial mesenchymal transition (EMT). 17-PAG also downregulated the HSP90 client proteins, including Her2, EGFR, C-Raf, AKT, p-AKT, and CDK4. Animal assays confirmed that 17-PAG shows strong anti-tumor effects with no obvious organ toxicity in DU-145 cell xenografted nude mice. These results provide us with a potential target for treating androgen-independent prostate cancer in a safe and effective manner.

American journal of cancer research. 2015 Sep 15*** epublish ***

Ruixian Peng, Zhenyu Li, Zhiyuan Lin, Yang Wang, Wei Wang, Bo Hu, Xilong Wang, Jun Zhang, Yangyun Wang, Renyuan Zhou, Chunhua Lu, Yuemao Shen, Jifeng Wang, Guowei Shi

Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University No. 44 West Wenhua Road, Jinan 250012, Shandong, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University No. 44 West Wenhua Road, Jinan 250012, Shandong, P. R. China., Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University No. 44 West Wenhua Road, Jinan 250012, Shandong, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China., Department of Urology, The Fifth People's Hospital of Shanghai, Fudan University Shanghai 200240, P. R. China ; Urology Research Center, Fudan University Shanghai 200240, P. R. China.