Disulfiram/copper shows potent cytotoxic effects on myelodysplastic syndromes via inducing Bip-mediated apoptosis and suppressing autophagy

• DOI: 10.1016/j.ejphar.2021.174107
• Publication Date: 2021-04-16T15:44:23Z
• Authors: Jie Zha; Silei Bi; Manman Deng; Kai Chen; Pengcheng Shi; Liying Feng; Jixiang He; Xuan Pu; Chengcen Guo; Haijun Zhao; Zhifeng Li; Yirong Jiang; Haihan Song; Bing Xu
• Keywords: Mice, Inbred BALB C; 0303 health sciences; Cell Cycle; Mice, Nude; Antineoplastic Agents; Apoptosis; Endoplasmic Reticulum Stress; Mitochondria; 3. Good health; Mice, Inbred C57BL; 03 medical and health sciences; Cell Line, Tumor; Myelodysplastic Syndromes; Disulfiram; Autophagy; Animals; Humans; Female; Endoplasmic Reticulum Chaperone BiP; Proto-Oncogene Proteins c-akt; Copper; Heat-Shock Proteins; Cell Proliferation

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 MDS in vitro and in vivo with 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.