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

• Type of Material: Article
• Authors: Yang Yang, Huazhong University of Science & Technology; Kenza Mamouni, Georgia Cancer Center; Xin Li, Georgia Cancer Center; Yanhua Chen, Georgia Cancer Center; Sravan Kavuri, Augusta University; Yuhong Du, Emory University; Haian Fu, Emory University; Omer Kucuk, Emory University; Daqing Wu, Emory University
• Language: English
• Date: 2018-09-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1535-7163.MCT-17-1176
• Title of Journal or Parent Work: Molecular Cancer Therapeutics
• ISSN: 1535-7163
• Volume: 17
• Issue: 9
• Start Page: 1859
• End Page: 1870
• Grant/Funding Information: This work is partially supported by the National Cancer Institute grants 1R41CA186498-01A1, 1R41CA206725-01A1 and 1R41CA217491-01A1; University of Georgia-Augusta University Cancer Research Initiative Award; and Georgia Cancer Center Startup Fund (D. Wu); National Natural Science Foundation of China grant 81401759 (Y. Chen).
• Keywords: NEUROENDOCRINE TUMORS; LUNG-CANCER; GROWTH; EXPRESSION; ANDROGEN RECEPTOR; Oncology; CELLS; THERAPEUTIC TARGET; CARCINOMA; Science & Technology; Life Sciences & Biomedicine; ACUTE MYELOID-LEUKEMIA; ANTAGONIST
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

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.