Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
Department of Clinical Research Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China.
Biomed Pharmacother. 2024 Jun;175:116727. doi: 10.1016/j.biopha.2024.116727. Epub 2024 May 10.
Myelodysplastic syndromes (MDS) encompass a collection of clonal hematopoietic malignancies distinguished by the depletion of peripheral blood cells. The treatment of MDS is hindered by the advanced age of patients, with a restricted repertoire of drugs currently accessible for therapeutic intervention. In this study, we found that ES-Cu strongly inhibited the viability of MDS cell lines and activated cuproptosis in a copper-dependent manner. Importantly, ferroptosis inducer IKE synergistically enhanced ES-Cu-mediated cytotoxicity both in vitro and in vivo. Of note, the combination of IKE and ES-Cu intensively impaired mitochondrial homeostasis with increased mitochondrial ROS, MMP hyperpolarized, down-regulated iron-sulfur proteins and declined oxygen consumption rate. Additionally, ES-Cu/IKE treatment could enhance the lipoylation-dependent oligomerization of the DLAT. To elucidate the specific order of events in the synergistic cell death, inhibitors of ferroptosis and cuproptosis were utilized to further characterize the basis of cell death. Cell viability assays showed that the glutathione and its precursor N-acetylcysteine could significantly rescue the cell death under either mono or combination treatment, demonstrating that GSH acts at the crossing point in the regulation network of cuproptosis and ferroptosis. Significantly, the reconstitution of xCT expression and knockdown of FDX1 cells have been found to contribute to the tolerance of mono treatment but have little recovery impact on the combined treatment. Collectively, these findings suggest that a synergistic interaction leading to the induction of multiple programmed cell death pathways could be a promising approach to enhance the effectiveness of therapy for MDS.
骨髓增生异常综合征（MDS）是一组克隆性造血恶性肿瘤，其特征为外周血细胞减少。由于患者年龄较大，治疗方法受到限制，目前可用于治疗干预的药物种类有限，因此 MDS 的治疗受到阻碍。在这项研究中，我们发现 ES-Cu 可强烈抑制 MDS 细胞系的活力，并以铜依赖性方式激活铜敏性细胞死亡。重要的是，铁死亡诱导剂 IKE 可协同增强 ES-Cu 介导的体外和体内细胞毒性。值得注意的是，IKE 和 ES-Cu 的联合使用会严重破坏线粒体稳态，导致线粒体 ROS 增加、MMP 超极化、铁硫蛋白下调和耗氧量降低。此外，ES-Cu/IKE 处理可增强 DLAT 的依赖于 lipoylation 的寡聚化。为了阐明协同细胞死亡中特定事件的顺序，使用铁死亡和铜敏性细胞死亡抑制剂进一步表征细胞死亡的基础。细胞活力测定表明，谷胱甘肽及其前体 N-乙酰半胱氨酸在单一或联合治疗下均可显著挽救细胞死亡，表明 GSH 在铜敏性细胞死亡和铁死亡调节网络的交汇点发挥作用。重要的是，我们发现 xCT 表达的重建和 FDX1 细胞的敲低有助于对单一治疗的耐受，但对联合治疗的恢复影响不大。总之，这些发现表明，诱导多种程序性细胞死亡途径的协同相互作用可能是增强 MDS 治疗效果的一种有前途的方法。
