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.