Potential Roles of Melatonin in Doxorubicin-Induced Cardiotoxicity: From Cellular Mechanisms to Clinical Application

Abstract

Doxorubicin is a potent chemotherapeutic drug; however, its clinical application has been limited due to its cardiotoxicity. One of the major mechanisms of doxorubicin-induced cardiotoxicity is the induction of oxidative stress. Evidence from in vitro and in vivo studies demonstrates that melatonin attenuated the increase in ROS production and lipid peroxidation from doxorubicin. Melatonin has been shown to exert protective effects on mitochondria damaged by doxorubicin via attenuating the depolarization of the mitochondrial membrane, restoring ATP production, and maintaining mitochondrial biogenesis. Doxorubicin increased mitochondrial fragmentation which impaired mitochondrial function; however, these adverse effects were reversed by melatonin. Melatonin also modulated cell death pathways by suppressing apoptotic and ferroptotic cell death caused by doxorubicin. These beneficial effects of melatonin could be responsible for the attenuation of changes in ECG, left ventricular dysfunction, and hemodynamic deterioration caused by doxorubicin. Despite these potential benefits, clinical evidence regarding the impact of melatonin in reducing cardiotoxicity induced by doxorubicin is still limited. Further clinical studies are justified to evaluate the efficacy of melatonin in protecting against doxorubicin-induced cardiotoxicity. This valuable information can be used to warrant the use of melatonin in a clinical setting under this condition.