title: Niclosamide enhances abiraterone treatment via inhibition of androgen receptor variants in castration resistant prostate cancer.
abstract: Considerable evidence from both clinical and experimental studies suggests that androgen receptor variants, particularly androgen receptor variant 7 (AR-V7), are critical in the induction of resistance to enzalutamide and abiraterone. In this study, we investigated the role of AR-V7 in the cross-resistance of enzalutamide and abiraterone and examined if inhibition of AR-V7 can improve abiraterone treatment response. We found that enzalutamide-resistant cells are cross-resistant to abiraterone, and that AR-V7 confers resistance to abiraterone. Knock down of AR-V7 by siRNA in abiraterone resistant CWR22Rv1 and C4-2B MDVR cells restored their sensitivity to abiraterone, indicating that AR-V7 is involved in abiraterone resistance. Abiraterone resistant prostate cancer cells generated by chronic treatment with abiraterone showed enhanced AR-V7 protein expression. Niclosamide, an FDA-approved antihelminthic drug that has been previously identified as a potent inhibitor of AR-V7, re-sensitizes resistant cells to abiraterone treatment in vitro and in vivo. In summary, this preclinical study suggests that overexpression of AR-V7 contributes to resistance to abiraterone, and supports the development of combination of abiraterone with niclosamide as a potential treatment for advanced castration resistant prostate cancer.
authors.affiliation: Department of Urology, University of California Davis, CA, USA.
authors.forename: Chengfei
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Urology, University of California Davis, CA, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Armstrong
authors.affiliation: Department of Urology, University of California Davis, CA, USA.|Graduate Program in Pharmacology and Toxicology, University of California Davis, CA, USA.
authors.forename: Yezi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Urology, University of California Davis, CA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Lou
authors.affiliation: Department of Urology, University of California Davis, CA, USA.|Graduate Program in Pharmacology and Toxicology, University of California Davis, CA, USA.|UC Davis Comprehensive Cancer Center, University of California Davis, CA, USA.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Gao
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000736:Androstenes / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D014644:Genetic Variation; D006801:Humans; D008297:Male; D016513:Mice, SCID; D009534:Niclosamide / Q000494:pharmacology*; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D011944:Receptors, Androgen / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D000736:Androstenes; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; D009534:Niclosamide; C540278:enzalutamide; C089740:abiraterone
keywords: abiraterone; androgen receptor variant; niclosamide; prostate cancer; resistance