title: Discovery of Potent 17β-Hydroxywithanolides for Castration-Resistant Prostate Cancer by High-Throughput Screening of a Natural Products Library for Androgen-Induced Gene Expression Inhibitors.
abstract: 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.
authors: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 East Valencia Road, Tucson, Arizona 85706, United States.
authors: Ya-Ming
authors: YM
authors: Xu
authors: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 East Valencia Road, Tucson, Arizona 85706, United States.
authors: Manping X
authors: MX
authors: Liu
authors: NuvoGen Research LLC , P.O. Box 64326, Tucson, Arizona 85728, United States.
authors: Nathan
authors: N
authors: Grunow
authors: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 East Valencia Road, Tucson, Arizona 85706, United States.
authors: E M Kithsiri
authors: EM
authors: Wijeratne
authors: University of Arizona Cancer Center , 1515 North Campbell Avenue, Tucson, Arizona 85724, United States.
authors: Gillian
authors: G
authors: Paine-Murrieta
authors: NuvoGen Research LLC , P.O. Box 64326, Tucson, Arizona 85728, United States.
authors: Stephen
authors: S
authors: Felder
authors: NuvoGen Research LLC , P.O. Box 64326, Tucson, Arizona 85728, United States.
authors: Richard M
authors: RM
authors: Kris
authors: Natural Products Center, School of Natural Resources and the Environment, College of Agriculture and Life Sciences, University of Arizona , 250 East Valencia Road, Tucson, Arizona 85706, United States.
authors: A A Leslie
authors: AA
authors: Gunatilaka
mesh_terms: D000728:Androgens / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001688:Biological Products / Q000737:chemistry*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D064593:Heterografts; D057166:High-Throughput Screening Assays; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D008297:Male; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D013329:Structure-Activity Relationship; D054358:Withanolides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D001688:Biological Products; D050783:Proto-Oncogene Proteins c-ets; D011944:Receptors, Androgen; C403974:SPDEF protein, human; D054358:Withanolides; C000603353:physachenolide C; C000595667:KLK2 protein, human; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen