Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital &Institute, Beijing 100142, China.
Acta Pharmacol Sin. 2017 Sep;38(9):1282-1296. doi: 10.1038/aps.2017.24. Epub 2017 Jun 26.
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·d) 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·d) and DEX (8 mg·kg·d) 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.
最近的证据表明，多巴胺 D2 样受体（D2DR）拮抗剂，如三氟拉嗪和硫利达嗪，对癌症治疗和抑制癌症干细胞样细胞（CSCs）有效。在这项研究中，我们研究了地塞米松（DEX）和舒必利（SUL）联合治疗对耐药和转移性乳腺癌的抗癌作用，并进一步探讨了其潜在机制。SUL（25、100mg·kg·d）单独口服给药不能抑制人乳腺癌 MCF-7/Adr 异种移植模型中的肿瘤生长，但在体外和体内剂量依赖性地降低了 CSCs 的比例。相比之下，SUL（50mg·kg·d）和 DEX（8mg·kg·d）联合治疗显著抑制 MCF-7/Adr 异种移植模型中的肿瘤生长，同时对小鼠转移性乳腺癌 4T1 异种移植模型中的全身毒性和肺转移有很小的影响。在分析的转移相关生物标志物中，联合治疗显著降低了 MMP-2 的水平，但增加了 4T1 异种移植肿瘤中 E-钙黏蛋白的水平。此外，联合治疗显著抑制了 4T1 和人乳腺癌 MDA-MB-231 细胞在体外的集落形成、迁移和侵袭。在联合治疗中加入特异性 D2DR 激动剂 7-OH-DPAT 可逆转体内增强的抗癌作用和肿瘤组织中 CSC 群体的丢失。我们的数据表明，SUL 通过拮抗 D2DR，显著增强了 DEX 治疗耐药和转移性乳腺癌的疗效，这可能是由于 CSCs 的根除。
