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

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          Abstract

          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.

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          Author and article information

          Journal
          101132535
          30097
          Mol Cancer Ther
          Mol. Cancer Ther.
          Molecular cancer therapeutics
          1535-7163
          1538-8514
          20 June 2018
          15 June 2018
          September 2018
          01 September 2019
          : 17
          : 9
          : 1859-1870
          Affiliations
          [1 ]Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
          [2 ]Molecular Oncology and Biomarkers Program, Georgia Cancer Center; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, USA
          [3 ]Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
          [4 ]Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA
          [5 ]Department of Pharmacology and Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, USA
          [6 ]Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA
          [7 ]MetCure Therapeutics LLC, Atlanta, GA, USA
          Author notes
          [§ ]Correspondence to: Dr. Daqing Wu, Georgia Cancer Center and Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA; dwu@ 123456augusta.edu ; Phone: (706)723-4137
          Article
          PMC6125160 PMC6125160 6125160 nihpa976278
          10.1158/1535-7163.MCT-17-1176
          6125160
          29907594
          afcb4d5c-f3aa-4803-93e2-0df848ba01df
          History
          Categories
          Article

          bone metastasis,androgen receptor,bromocriptine,dopamine D2 receptor,docetaxel,Prostate cancer

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