Disulfiram/copper shows potent cytotoxic effects on myelodysplastic syndromes via inducing Bip-mediated apoptosis and suppressing autophagy.
Disulfiram/copper shows potent cytotoxic effects on myelodysplastic syndromes via inducing Bip-mediated apoptosis and suppressing autophagy.
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DOI：
10.1016/j.ejphar.2021.174107
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发表时间：
2021-04
影响因子：
5
通讯作者：
Jie Zha;Silei Bi;Manman Deng;Kai Chen;P. Shi;Liying Feng;Jixiang He;X. Pu;Chengcen Guo;Haijun Zhao;Zhifeng Li;Yirong Jiang;Haihan Song;Bing Xu
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文献类型：
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作者：
Jie Zha;Silei Bi;Manman Deng;Kai Chen;P. Shi;Liying Feng;Jixiang He;X. Pu;Chengcen Guo;Haijun Zhao;Zhifeng Li;Yirong Jiang;Haihan Song;Bing Xu
骨髓增生异常综合征（MDS）患者对低甲基化药物（HMAs）抵抗或无反应，结果非常差，并且没有有效的治疗策略。因此，新的治疗方法是迫切需要的MDS患者窝藏不良预后因素。再利用双硫仑（DSF），一种酒精滥用药物，与或不与铜（Cu）作为一种候选的抗肿瘤治疗在各种恶性肿瘤中引起了相当大的关注。然而，DSF在存在或不存在Cu的情况下对MDS的影响尚未报道。在这项研究中，我们发现DSF单药治疗对MDS临床前模型显示出轻微的细胞毒性作用。然而，在体外和体内，在存在Cu的情况下，DSF的抗肿瘤活性显著增强，安全性最低。DSF/Cu联合作用可使MDS细胞周期阻滞于G 0/G1期，并伴有S期细胞减少。因此，与DSF和Cu的共同处理下调了Cyclin D1和Cyclin A2的表达，而这种组合上调了P21和P27的水平。从机制上讲，DSF/Cu的抗MDS有效性可能与ER应激相关Bip通路的激活和Akt通路的失活相关。此外，DSF/Cu对MDS细胞自噬过程的抑制也有助于其细胞毒性。总之，这些发现提供了令人印象深刻的证据，表明DSF/Cu复合物在MDS临床前模型上显示出有效的抗肿瘤功效，代表了MDS患者的潜在替代疗法，并在临床背景下进行进一步研究。
Patients with myelodysplastic syndromes (MDS) who resist or fail to respond to hypomethylating agents (HMAs) show very poor outcomes and have no effective treatment strategies. Therefore, new therapeutic approaches are urgently needed for MDS patients harboring adverse prognostic factors. Repurposing disulfiram (DSF), an alcohol-abuse drug, with or without Copper (Cu) has attracted considerable attentions as a candidate anti-tumor therapy in diverse malignancies. However, the effect of DSF in the presence or absence of Cu on MDS has not been reported yet. In this study, we found that monotherapy with DSF showed mild cytotoxic effects on MDS preclinical models. However, the anti-tumor activity of DSF was significantly enhanced in the presence of Cu in MDSin vitroandin vivowith minimal safety profiles. DSF/Cu combination blocked MDS cell cycle progression at the G0/G1 phase, accompanied by reduction of the S phase. Accordingly, co-treatment with DSF and Cu downregulated the expression of Cyclin D1 and Cyclin A2, whereas this combination upregulated the level of P21 and P27. Mechanistically, the anti-MDS effectiveness of DSF/Cu was potentially associated with activation of the ER stress-related Bip pathway and inactivation of the Akt pathway. In addition, inhibition of autophagy process also contributed to the cytotoxicity of DSF/Cu in MDS cells. In conclusion, these findings provide impressive evidence that the DSF/Cu complex shows potent anti-tumor efficacies on MDS preclinical models, representing a potential alternative therapy for MDS patients and warranting further investigation in clinical contexts.