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 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..

In Vitro Effect and Mechanism of Action of Ergot Alkaloid Dihydroergocristine in Chemoresistant Prostate Cancer Cells

“…In a recent study, we provided the first evidence demonstrating that DRD2 expression is inversely associated with clinical PCa progression. We further identified bromocriptine, a semisynthetic ergot alkaloid, as a potential adjunct therapy to sensitize PCa cells to docetaxel chemotherapy (35). These observations supported the notion that DRD2 agonism may represent a novel strategy to overcome chemoresistance.…”

“…Although our understanding of the biology of dopamine receptor signaling in cancer progression is still rudimentary and sometimes controversial, mounting experimental and clinical evidence has indicated that the dysregulation of dopamine receptor signaling is associated with the progression of human cancers, including PCa (35,(57)(58)(59)(60). Some epidemiologic studies further suggested a correlation between psychotic disorders in which dopaminergic drugs are applied and the risk of cancer, of particular note, a reduced risk of PCa (61,62).…”

Wnt5a induces and maintains prostate cancer cells dormancy in bone

“…Since dormant cells are known for their resistance against drug treatment, we further investigated the effect of chemotherapy on Wnt5a-induced dormant cells in bone using docetaxel, the most commonly used drug for the treatment of bone metastatic PCa (Banerjee et al, 2007; Yang et al, 2018). First, antimetastatic efficacy of docetaxel in bone metastasis of PCa was demonstrated by the finding that the tumor burden of mice treated with docetaxel was significantly reduced compared with that in the vehicle (Fig.…”

D2 dopamine receptor gene (DRD2) Taq1A (rs1800497) affects bone density

“…In mice study, administration of D2 receptor antagonist amisulpride to diabetic mice restored trabecular bone structure to near normal and partially reversed downregulation of lysyl oxidase 31 . Moreover, bromocriptine, a potent D2 agonist has been widely used in the treatment of bone metastatic prostate cancer 32 . Several studies have found that people with the DRD2 rs1800497 T allele had a higher prolactin level during antipsychotics use 20 .…”