title: The HSP90 inhibitor 17-PAG effectively inhibits the proliferation and migration of androgen-independent prostate cancer cells.
abstract: 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.
authors.affiliation: 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.
authors.forename: Ruixian
authors.initials: R
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Xilong
authors.initials: X
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Yangyun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Renyuan
authors.initials: R
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Yuemao
authors.initials: Y
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Guowei
authors.initials: G
authors.lastname: Shi
keywords: Geldanamycin derivative; androgen independent; chemotherapy; hsp90; prostate cancer