Niclosamide enhances abiraterone treatment via inhibition of androgen receptor variants in castration resistant prostate cancer
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Chengfei Liu1, Cameron Armstrong1, Yezi Zhu1,2, Wei Lou1, Allen C. Gao1,2,3
1Department of Urology, University of California Davis, CA, USA
2Graduate Program in Pharmacology and Toxicology, University of California Davis, CA, USA
3UC Davis Comprehensive Cancer Center, University of California Davis, CA, USA
Allen C. Gao, e-mail: [email protected]
Keywords: prostate cancer, niclosamide, abiraterone, androgen receptor variant, resistance
Received: December 10, 2015 Accepted: March 10, 2016 Published: March 30, 2016
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.
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