Original Article

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drugresistant and metastatic breast cancer

Jian LI, Qing-yu YAO, Jun-sheng XUE, Li-jie WANG, Yin YUAN, Xiu-yun TIAN, Hong SU, Si-yuan WANG, Wen-jun CHEN, Wei LU, Tian-yan ZHOU
DOI: 10.1038/aps.2017.24


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.
Keywords: breast cancer; dexamethasone; sulpiride; dopamine-D2 receptor; combination therapy; drug-resistance; metastasis; cancer stem cells; 7-OH-DPAT

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