Abstract
Homeostatic regulation of cardiomyocytes plays a crucial role in maintaining the normal physiological activity of cardiac tissue. Severe cardiotoxicity results in cardiac diseases including but not limited to arrhythmia, myocardial infarction and myocardial hypertrophy. Drug-induced cardiotoxicity limits or forbids further use of the implicated drugs. Such drugs that are currently available in the clinic include anti-tumor drugs (doxorubicin, cisplatin, trastuzumab, etc.), antidiabetic drugs (rosiglitazone and pioglitazone), and an antiviral drug (zidovudine). This review focused on cardiomyocyte death forms and related mechanisms underlying clinical drug-induced cardiotoxicity, including apoptosis, autophagy, necrosis, necroptosis, pryoptosis, and ferroptosis. The key proteins involved in cardiomyocyte death signaling were discussed and evaluated, aiming to provide a theoretical basis and target for the prevention and treatment of drug-induced cardiotoxicity in the clinical practice.
Highlights
Cardiotoxicity commonly refers to toxicity that has a detrimental impact on the heart, which might lead to myocardiopathy such as arrhythmia, myocardial infarction and myocardial hypertrophy
Cardiotoxicity is a major concern when evaluating whether drugs can be put on the market during preclinical research and is an important reason for post-approval drug withdrawal
reactive oxygen species (ROS) serves a main driver in drug-induced cardiotoxicity, and thereby many antioxidants have undergone preclinical development or clinically research for cardiotoxicity
Summary
Cardiotoxicity commonly refers to toxicity that has a detrimental impact on the heart, which might lead to myocardiopathy such as arrhythmia, myocardial infarction and myocardial hypertrophy. Another study discovered that the levels of iron and ROS were upregulated in DOX-treated cardiomyocytes, which induced the mitochondrial apoptosis through caspase-3 activation and cytochrome C release (Childs et al, 2002). A recent study showed that the four death reporters (Fas, TNFR1, DR4, and DR5) were significant increased at the mRNA and protein levels after DOX treatment in induced pluripotent stem cells (iPS) -derived cardiomyocytes (Zhao and Zhang, 2017).
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