Department of Hematology, The First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, China; Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, 361003, China.
Department of Hematology, Heze Municipal Hospital, Heze, 274031, China.
Eur J Pharmacol. 2021 Jul 5;902:174107. doi: 10.1016/j.ejphar.2021.174107. Epub 2021 Apr 16.
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.
患有骨髓增生异常综合征（MDS）的患者对低甲基化剂（HMAs）有抵抗或无反应，其预后极差，且无有效的治疗策略。因此，对于存在不良预后因素的 MDS 患者，迫切需要新的治疗方法。重新利用戒酒硫（DSF），一种酒精滥用药物，与铜（Cu）联合或不联合使用，已引起人们对多种恶性肿瘤候选抗肿瘤治疗的极大关注。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 MDS 体外和体内，DSF 在 Cu 存在时的抗肿瘤活性显著增强，且安全性特征最小。DSF/Cu 联合阻断 MDS 细胞周期在 G0/G1 期进展，同时减少 S 期。相应地，DSF 和 Cu 的共同治疗下调了细胞周期蛋白 D1 和细胞周期蛋白 A2 的表达，而这种联合上调了 P21 和 P27 的水平。从机制上讲，DSF/Cu 对 MDS 的抗 MDS 作用可能与 ER 应激相关 Bip 途径的激活和 Akt 途径的失活有关。此外，自噬过程的抑制也有助于 DSF/Cu 在 MDS 细胞中的细胞毒性。总之，这些发现提供了令人印象深刻的证据，表明 DSF/Cu 复合物对 MDS 临床前模型具有强大的抗肿瘤疗效，为 MDS 患者提供了一种潜在的替代治疗方法，并值得在临床环境中进一步研究。
