Niclosamide Inhibits Androgen Receptor Variants Expression and Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer

被引:302
作者
Liu, Chengfei [1 ]
Lou, Wei [1 ]
Zhu, Yezi [1 ,2 ]
Nadiminty, Nagalakshmi [1 ]
Schwartz, Chad T. [1 ]
Evans, Christopher P. [1 ,3 ]
Gao, Allen C. [1 ,2 ,3 ]
机构
[1] Univ Calif Davis, Dept Urol, Sacramento, CA 95817 USA
[2] Univ Calif Davis, Grad Program Pharmacol & Toxicol, Sacramento, CA 95817 USA
[3] Univ Calif Davis, UC Davis Comprehens Canc Ctr, Sacramento, CA 95817 USA
关键词
INCREASED SURVIVAL; SPLICE VARIANT; MDV3100; CELLS; SUPPRESSION; PROGRESSION; ABIRATERONE; MODULATORS; AUTOPHAGY; MUTATION;
D O I
10.1158/1078-0432.CCR-13-3296
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Enzalutamide, a second-generation antiandrogen, was recently approved for the treatment of castration-resistant prostate cancer (CRPC) in patients who no longer respond to docetaxel. Despite these advances that provide temporary respite, resistance to enzalutamide occurs frequently. Androgen receptor (AR) splice variants such as AR-V7 have recently been shown to drive castration-resistant growth and resistance to enzalutamide. This study was designed to identify inhibitors of AR variants and test its ability to overcome resistance to enzalutamide. Experimental Design: The drug screening was conducted using luciferase activity assay to determine the activity of AR-V7 after treatment with the compounds in the Prestwick Chemical Library, which contains about 1,120 FDA-approved drugs. The effects of the identified inhibitors on AR-V7 activity and enzalutamide sensitivity were characterized in CRPC and enzalutamide-resistant prostate cancer cells in vitro and in vivo. Results: Niclosamide, an FDA-approved antihelminthic drug, was identified as a potent AR-V7 inhibitor in prostate cancer cells. Niclosamide significantly downregulated AR-V7 protein expression by protein degradation through a proteasome-dependent pathway. Niclosamide also inhibited AR-V7 transcription activity and reduced the recruitment of AR-V7 to the PSA promoter. Niclosamide inhibited prostate cancer cell growth in vitro and tumor growth in vivo. Furthermore, the combination of niclosamide and enzalutamide resulted in significant inhibition of enzalutamide-resistant tumor growth, suggesting that niclosamide enhances enzalutamide therapy and overcomes enzalutamide resistance in CRPC cells. Conclusions: Niclosamide was identified as a novel inhibitor of AR variants. Our findings offer preclinical validation of niclosamide as a promising inhibitor of AR variants to treat, either alone or in combination with current antiandrogen therapies, patients with advanced prostate cancer, especially those resistant to enzalutamide. (C) 2014 AACR.
引用
收藏
页码:3198 / 3210
页数:13
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