Docetaxel resistance remains a major obstacle in the treatment of prostate cancer bone metastasis. In this study, we demonstrate that the dopamine D2 receptor (DRD2) agonist bromocriptine effectively enhances docetaxel efficacy and suppresses skeletal growth of prostate cancer in preclinical models. DRD2 is ubiquitously expressed in prostate cancer cell lines and significantly reduced in prostate cancer tissues with high Gleason score. Bromocriptine has weak to moderate cytotoxicity in prostate cancer cells, but effectively induces cell-cycle arrest. At the molecular level, bromocriptine inhibits the expression of c-Myc, E2F-1, and survivin and increases the expression of p53, p21, and p27. Intriguingly, bromocriptine markedly reduces androgen receptor levels, partially through Hsp90-mediated protein degradation. The combination of bromocriptine and docetaxel demonstrates enhanced in vitro cytotoxicity in prostate cancer cells and significantly retards the skeletal growth of C4-2-Luc tumors in mice. Collectively, these results provide the first experimental evidence for repurposing bromocriptine as an effective adjunct therapy to enhance docetaxel efficacy in prostate cancer. Mol Cancer Ther; 17(9); 1859–70. ©2018 AACR.

中文翻译：

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重新定位多巴胺 D2 受体激动剂溴隐亭以增强多西紫杉醇化疗和治疗骨转移性前列腺癌

多西紫杉醇耐药性仍然是治疗前列腺癌骨转移的主要障碍。在这项研究中，我们证明多巴胺 D2 受体 (DRD2) 激动剂溴隐亭可有效增强多西他赛疗效并抑制临床前模型中前列腺癌的骨骼生长。DRD2 在前列腺癌细胞系中普遍表达，在具有高 Gleason 评分的前列腺癌组织中显着降低。Bromocriptine 在前列腺癌细胞中具有弱至中度的细胞毒性，但可有效诱导细胞周期停滞。在分子水平上，溴隐亭抑制c-Myc、E2F-1和survivin的表达，增加p53、p21和p27的表达。有趣的是，溴隐亭显着降低雄激素受体水平，部分是通过 Hsp90 介导的蛋白质降解。溴隐亭和多西他赛的组合在前列腺癌细胞中表现出增强的体外细胞毒性，并显着延缓小鼠 C4-2-Luc 肿瘤的骨骼生长。总的来说，这些结果为将溴隐亭重新用作有效的辅助疗法以增强多西紫杉醇在前列腺癌中的疗效提供了第一个实验证据。Mol 癌症疗法；17(9); 1859–70。©2018 AACR。