Repositioning dopamine D2 receptor agonist bromocriptine to enhance docetaxel chemotherapy and treat bone metastatic prostate cancer

Yang Yang, Kenza Mamouni, Xin Li, Yanhua Chen, Sravan Kumar Kavuri, Yuhong Du, Haian Fu, Omer Kucuk, Daqing Wu

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1859-1870
Number of pages12
JournalMolecular cancer therapeutics
Volume17
Issue number9
DOIs
StatePublished - Sep 2018

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docetaxel
Bromocriptine
Dopamine D2 Receptors
Dopamine Agonists
Prostatic Neoplasms
Bone and Bones
Drug Therapy
Bone Neoplasms
Neoplasm Grading
Androgen Receptors
Growth
Cell Cycle Checkpoints
Proteolysis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Repositioning dopamine D2 receptor agonist bromocriptine to enhance docetaxel chemotherapy and treat bone metastatic prostate cancer. / Yang, Yang; Mamouni, Kenza; Li, Xin; Chen, Yanhua; Kavuri, Sravan Kumar; Du, Yuhong; Fu, Haian; Kucuk, Omer; Wu, Daqing.

In: Molecular cancer therapeutics, Vol. 17, No. 9, 09.2018, p. 1859-1870.

Research output: Contribution to journalArticle

Yang, Yang ; Mamouni, Kenza ; Li, Xin ; Chen, Yanhua ; Kavuri, Sravan Kumar ; Du, Yuhong ; Fu, Haian ; Kucuk, Omer ; Wu, Daqing. / Repositioning dopamine D2 receptor agonist bromocriptine to enhance docetaxel chemotherapy and treat bone metastatic prostate cancer. In: Molecular cancer therapeutics. 2018 ; Vol. 17, No. 9. pp. 1859-1870.
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