withanolides and Prostatic-Neoplasms--Castration-Resistant

Prostate cancer (PC) is the second most prevalent cancer among men in Western societies, and those who develop metastatic castration-resistant PC (CRPC) invariably succumb to the disease. The need for effective treatments for CRPC is a pressing concern, especially due to limited durable responses with currently employed therapies. Here, we demonstrate the successful application of a high-throughput gene-expression profiling assay directly targeting genes of the androgen receptor pathway to screen a natural products library leading to the identification of 17β-hydroxywithanolides 1-5, of which physachenolide D (5) exhibited potent and selective in vitro activity against two PC cell lines, LNCaP and PC-3. Epoxidation of 5 afforded physachenolide C (6) with higher potency and stability. Structure-activity relationships for withanolides as potential anti-PC agents are presented together with in vivo efficacy studies on compound 6, suggesting that 17β-hydroxywithanolides are promising candidates for further development as CRPC therapeutics.

Topics: Androgens; Animals; Antineoplastic Agents; Biological Products; Cell Line, Tumor; Drug Screening Assays, Antitumor; Gene Expression; Gene Expression Profiling; Heterografts; High-Throughput Screening Assays; Humans; Kallikreins; Male; Mice, SCID; Neoplasm Transplantation; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-ets; Receptors, Androgen; Structure-Activity Relationship; Withanolides