Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, 117984Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Hematologic Disease Laboratory, Hematology Center, Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics (Capital Medical University), Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, 117984Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
Hum Exp Toxicol. 2022 Jan-Dec;41:9603271211064537. doi: 10.1177/09603271211064537.
Arsenic trioxide (ATO) has been found to be effective in acute promyelocytic leukemia. However, ATO-induced severe cardiotoxicity limits its clinical application. To date, the mechanisms of ATO-induced cardiotoxicity remain unclear. It is hypothesized that ferroptosis may trigger ATO-induced cardiotoxicity; however, this has not yet been investigated. To clarify this hypothesis, rat cardiomyocyte H9c2 cells were treated with ATO with or without ferrostain-1 (Fer-1). The results indicated that ATO exposure induced H9c2 cell death and apoptosis, and the ferroptosis inhibitor Fer-1, administered for 24 h before ATO exposure, suppressed ATO-induced cell death, and apoptosis, as determined by Annexin V-APC/7-AAD apoptosis assay. Furthermore, Fer-1 displayed a cardioprotective effect through inhibiting the ATO-induced production of intracellular reactive oxygen species, improving the ATO-induced loss of the mitochondrial membrane potential, alleviating hyperactive endoplasmic reticulum stress, and alleviating the ATO-induced impairment in autophagy in H9c2 cells. Overall, the cardioprotective effect of Fer-1 against ATO-induced cell injury implies that ATO may trigger ferroptosis to induce cardiotoxicity. These findings lay the foundation for exploring the potential value of ferroptosis inhibitors against ATO-induced cardiotoxicity in the future.
三氧化二砷（ATO）已被证明对急性早幼粒细胞白血病有效。然而，ATO 诱导的严重心脏毒性限制了其临床应用。迄今为止，ATO 诱导的心脏毒性的机制仍不清楚。据推测，铁死亡可能引发 ATO 诱导的心脏毒性；然而，这尚未得到研究。为了阐明这一假设，用 ATO 或用 Fer-1（Ferrostain-1）处理大鼠心肌细胞 H9c2 细胞。结果表明，ATO 暴露诱导 H9c2 细胞死亡和凋亡，铁死亡抑制剂 Fer-1 在 ATO 暴露前 24 小时给药，可抑制 ATO 诱导的细胞死亡和凋亡，通过 Annexin V-APC/7-AAD 凋亡测定法确定。此外，Fer-1 通过抑制 ATO 诱导的细胞内活性氧的产生、改善 ATO 诱导的线粒体膜电位丧失、减轻过度活跃的内质网应激以及减轻 ATO 诱导的 H9c2 细胞自噬损伤，发挥心脏保护作用。总之，Fer-1 对 ATO 诱导的细胞损伤的心脏保护作用表明，ATO 可能引发铁死亡，从而导致心脏毒性。这些发现为未来探索铁死亡抑制剂对 ATO 诱导的心脏毒性的潜在价值奠定了基础。
