TY - JOUR AU - LI Jian AU - YAO Qing-yu AU - XUE Jun-sheng AU - WANG Li-jie AU - YUAN Yin AU - TIAN Xiu-yun AU - SU Hong AU - WANG Si-yuan AU - CHEN Wen-jun AU - LU Wei AU - ZHOU Tian-yan PY - 2017 TI - Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drugresistant and metastatic breast cancer JF - Acta Pharmacologica Sinica; Vol 38, No 9 (September 2017): Acta Pharmacologica Sinica Y2 - 2017 KW - N2 - Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg -1 ·d -1 ) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo . In contrast, combination therapy of SUL (50 mg·kg -1 ·d -1 ) and DEX (8 mg·kg -1 ·d -1 ) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro . Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs. UR - http://www.chinaphar.com/article/view/9660