Repositioning Dopamine D2 Receptor Agonist Bromocriptine to Enhance Docetaxel Chemotherapy and Treat Bone Metastatic Prostate Cancer.

Abstract

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.

• Authors: Yang Yang, Kenza Mamouni, Xin Li, Yanhua Chen, Sravan Kavuri, Yuhong Du, Haian Fu, Omer Kucuk, Daqing Wu
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 9 Pg. 1859-1870 (09 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 29907594 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Dopamine Agonists
• Receptors, Dopamine D2
• Docetaxel
• Bromocriptine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bone Neoplasms (drug therapy, metabolism, secondary)
• Bromocriptine (administration & dosage)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Docetaxel (administration & dosage)
• Dopamine Agonists (administration & dosage)
• Drug Repositioning
• Drug Synergism
• Humans
• Male
• Mice, Nude
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Receptors, Dopamine D2 (agonists, metabolism)
• Xenograft Model Antitumor Assays