Repositioning Dopamine D2 Receptor Agonist Bromocriptine to Enhance Docetaxel Chemotherapy and Treat Bone Metastatic Prostate Cancer.
Repositioning Dopamine D2 Receptor Agonist Bromocriptine to Enhance Docetaxel Chemotherapy and Treat Bone Metastatic Prostate Cancer.
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DOI：
10.1158/1535-7163.mct-17-1176
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发表时间：
2018-09
影响因子：
5.7
通讯作者：
Wu D
中科院分区：
文献类型：
--
作者：
Yang Y;Mamouni K;Li X;Chen Y;Kavuri S;Du Y;Fu H;Kucuk O;Wu D
多西他赛耐药仍然是前列腺癌骨转移治疗的主要障碍。在本研究中，我们在临床前模型中证明了多巴胺D2受体（DRD2）激动剂溴隐肽能有效增强多西他赛的疗效并抑制PCa的骨骼生长。DRD2在PCa细胞系中普遍表达，在Gleason评分高的PCa组织中，DRD2显著降低。溴隐亭对PCa细胞有弱至中度的细胞毒性，但能有效诱导细胞周期阻滞。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，溴隐亭显著降低雄激素受体（AR）水平，部分是通过热休克蛋白90 （Hsp90）介导的蛋白质降解。溴隐亭和多西紫杉醇联合使用增强了PCa细胞的体外细胞毒性，并显著延缓了小鼠C4-2-Luc肿瘤的骨骼生长。总的来说，这些结果为溴隐亭作为一种有效的辅助治疗来增强多西他赛在PCa中的疗效提供了第一个实验证据。
Docetaxel resistance remains a major obstacle in the treatment of prostate cancer (PCa) bone metastasis. In this study, we demonstrate that the dopamine D2 receptor (DRD2) agonist bromocriptine effectively enhances docetaxel efficacy and suppresses skeletal growth of PCa in preclinical models. DRD2 is ubiquitously expressed in PCa cell lines, and DRD2 is significantly reduced in PCa tissues with high Gleason score. Bromocriptine has weak to moderate cytotoxicity in PCa 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 (AR) levels, partially through heat-shock protein 90 (Hsp90)-mediated protein degradation. The combination of bromocriptine and docetaxel demonstrates enhanced in vitro cytotoxicity in PCa 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 PCa.