TY - JOUR
T1 - Repositioning dopamine D2 receptor agonist bromocriptine to enhance docetaxel chemotherapy and treat bone metastatic prostate cancer
AU - Yang, Yang
AU - Mamouni, Kenza
AU - Li, Xin
AU - Chen, Yanhua
AU - Kavuri, Sravan Kumar
AU - Du, Yuhong
AU - Fu, Haian
AU - Kucuk, Omer
AU - Wu, Daqing
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-17-1176
DO - 10.1158/1535-7163.MCT-17-1176
M3 - Article
C2 - 29907594
AN - SCOPUS:85051388015
SN - 1535-7163
VL - 17
SP - 1859
EP - 1870
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 9
ER -