Abnormal Ferroptosis in Myelodysplastic Syndrome
| Autor: | Shuwen Dong, Lanzhu Yue, Huaquan Wang, Qi Lv, Chunyan Liu, Zonghong Shao, Haiyue Niu, Huijuan Jiang, Jiaxi Liu, Limin Xing, Liyan Yang |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Programmed cell death Decitabine Pharmacology lcsh:RC254-282 Peripheral blood mononuclear cell 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Viability assay Original Research chemistry.chemical_classification Reactive oxygen species biology pyroptosis apoptosis Glutathione lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ferroptosis myelodysplastic syndrome Ferritin 030104 developmental biology Oncology chemistry Apoptosis 030220 oncology & carcinogenesis biology.protein decitabine medicine.drug |
| Zdroj: | Frontiers in Oncology Frontiers in Oncology, Vol 10 (2020) |
| ISSN: | 2234-943X |
| Popis: | Background Ferroptosis is a form of iron-dependent non-apoptotic cell death, with characteristics of loss of the activity of the lipid repair enzyme, glutathione (GSH) peroxidase 4 (GPX4), and accumulation of lethal reactive lipid oxygen species. The mechanism of ferroptosis in myelodysplastic syndrome (MDS) is unclear. Methods Cell viability assay, reactive oxygen species (ROS) assay, GSH assay, and GPX activity assay were performed to study the regulation of ferroptosis in MDS cells obtained from MDS patients, the iron overload model mice, and cell lines. Results The growth-inhibitory effect of decitabine could be partially reversed by ferrostatin-1 and iron-chelating agent [desferrioxamine (DFO)] in MDS cell lines. Erastin could increase the cytotoxicity of decitabine on MDS cells. The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1. The concentration of hemoglobin in peripheral blood of iron overload mice was negatively correlated with intracellular Fe2+ level and ferritin concentration. Iron overload (IO) led to decreased viability of bone marrow mononuclear cells (BMMNCs), which was negatively correlated with intracellular Fe2+ level. Ferrostatin-1 partially reversed the decline of cell viability in IO groups. The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in BMMNCs of IO mice. DFO could increase the level of GSH. Ferrostatin-1 and DFO could increase the GPX4 activity of BMMNCs in IO mice. Ferrostatin-1 could significantly reverse the growth-inhibitory effect of decitabine in MDS patients. Decitabine could significantly increase the ROS level in MDS groups, which could be inhibited by ferrostatin-1 or promoted by erastin. Ferrostatin-1 could significantly reverse the inhibitory effect of decitabine on GSH levels in MDS patients. Erastin combined with decitabine could further reduce the GSH level. Erastin could further decrease the activity of GPX4 compared with the decitabine group. Conclusion Ferroptosis may account for the main mechanisms of how decitabine induced death of MDS cells. Decitabine-induced ROS raise leads to ferroptosis in MDS cells by decreasing GSH level and GPX4 activity. |
| Databáze: | OpenAIRE |
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