Imatinib Mesylate (IMA) has been widely used to treat with chronic myeloid leukemia (CML). However, cardiotoxicity associated with IMA is included among the therapeutic strategies. The present study was aimed to discover whether ferroptosis, a programmed iron-dependent cell death, is involved in IMA-induced cardiotoxicity. In vivo, mouse model was established after treated with 25 mg/kg, 50 mg/kg and 100 mg/kg IMA. Serum CK, LDH, AST activities were determined. Cardiac tissues were examined by H&E and Oil Red O staining. MDA was measured to assess production of lipid peroxide. Tissue iron and GSH content were measured. In vitro, cell viability, mitochondria membrane potential, generation of reactive oxygen species (ROS) and cellular iron levels were performed to explore the mechanism of IMA. The in vivo results revealed that IMA treatment significantly increased serum CK, LDH and AST. H&E staining showed that IMA caused cardiac structural injuries. The dose-dependent decrease of GSH and increase of tissue iron and MDA were observed in IMA-treated groups. Oil Red O staining suggested obvious cardiac lipid accumulation after treated with IMA. In H9c2 cardiomyocytes, IMA significantly inhibited cell proliferation in a dose-dependent manner. Mitochondria membrane potential assay showed that IMA destroyed the mitochondrial function. Additionally, IMA increased the cellular ROS and iron levels. Furthermore, IMA down-regulated the expression of Nrf2 and up-regulated the expression of P53 and TfR. These results provided compelling evidence that ferroptosis participates in IMA-induced cardiotoxicity. Ferroptosis could be regarded as a target to protect against cardiotoxicity in IMA-exposed patients.
Keywords: Cardiotoxicity; Ferroptosis; Imatinib Mesylate; Mechanism; Nrf2 Pathways.
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