2. Academic Validation
  3. Elesclomol-copper synergizes with imidazole ketone erastin by promoting cuproptosis and ferroptosis in myelodysplastic syndromes

Elesclomol-copper synergizes with imidazole ketone erastin by promoting cuproptosis and ferroptosis in myelodysplastic syndromes

  • Biomed Pharmacother. 2024 Jun:175:116727. doi: 10.1016/j.biopha.2024.116727.
Yan Gao 1,  Feifan Jin 2,  Ping Zhang 1,  Cuiping Zheng 3,  Xiaoyan Zheng 4,  Jing Xie 5,  Ying Lu 6,  Xiangmin Tong 2,  Jing Du 7,  Junyu Zhang 8,  Ying Wang 9
Affiliations

Affiliations

  • 1 Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China.
  • 2 Department of Clinical Research Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China.
  • 3 Department of Hematology, Wenzhou Central Hospital, Wenzhou, Zhejiang, China.
  • 4 Department of Clinical Laboratory, Quzhou Hospital affiliated to Wenzhou Medical University, Quzhou, Zhejiang, China.
  • 5 Department of Clinical Laboratory, Taizhou First People's Hospital, Taizhou, Zhejiang, China.
  • 6 Department of Hematology, Affiliated People's Hospital of Ningbo University, Ningbo, Zhejiang, China.
  • 7 Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, China. Electronic address: dujing1@hmc.edu.cn.
  • 8 Department of Hematology, Lishui Central Hospital, Lishui, Zhejiang, China. Electronic address: zhangjunyu1116@163.com.
  • 9 Department of Clinical Research Center, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China. Electronic address: nancywangying@163.com.
PMID: 38733771 DOI: 10.1016/j.biopha.2024.116727
Abstract

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.

Keywords

Cuproptosis; ES-Cu; Ferroptosis; IKE; MDS.

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