Arsenic trioxide-induced cardiotoxicity triggers ferroptosis in cardiomyoblast cells

Abstract

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.

Melatonin ameliorates arsenic‐induced cardiotoxicity through the regulation of the Sirt1/Nrf2 pathway in rats

“…This insight suggests the role of Beclin‐1/Bcl‐2 interaction in the crosstalk between autophagy and apoptosis 75,76 . Induction of autophagy is triggered in cardiomyocytes during As exposure 77 . Our data revealed that As‐induced cardio autophagy was mediated by up‐regulating Beclin‐1 expression and LC3‐II/I ratio.…”

“…75,76 Induction of autophagy is triggered in cardiomyocytes during As exposure. 77 Our data revealed that As-induced cardio autophagy was mediated by upregulating Beclin-1 expression and LC3-II/I ratio. Here we report that, in addition to the induction of Beclin-1 expression, Bcl-2 was significantly reduced in As group.…”

Berberine hydrochloride alleviates imatinib mesylate – induced cardiotoxicity through the inhibition of Nrf2-dependent ferroptosis

“…32 Following this, studies found that ferroptosis also takes part in arsenic trioxide induced cardiotoxicity and 5-FU-induced cardiotoxicity by decreasing the mitochondrial membrane potential. 33,34 It has been reported that ferroptosis coupled with mitochondrial dysfunction is involved in neurodegenerative diseases via activating JNK1/2 and ERK1/2. 35 It can be concluded that mitochondria plays a critucal role in the whole process of the occurrence and development of ferroptosis.…”

Bioinorganic Modulators of Ferroptosis: A Review of Recent Findings

“…It also caused rat cardiomyocyte H9c2 cell death, which involved the promotion of oxidative stress and was preventable by ferroptosis inhibitor Fer-1. Although the compound could not be safely applied in acute promyelocytic leukemia treatment due to its toxicity, ferroptosis inhibitors could serve as a potential treatment of cardiotoxicity caused by exposure to arsenic trioxide [ 152 ]. A combined therapy against platinum-sensitive ovarian cancer was proposed, comprising arsenic trioxide and PARP (Poly (ADP-ribose) polymerase) inhibitors.…”