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Doxorubicin is an effective chemotherapeutic drug, but causes cardiotoxicity which limits its use. Oxidative stress, mitochondrial dysfunction, and inflammation are closely implicated in doxorubicin-induced cardiotoxicity (DIC). Necroptosis, a new form of programmed cell death, was also upregulated by doxorubicin, leading to cardiomyocyte death and cardiac dysfunction. Donepezil, an acetylcholinesterase inhibitor, exerted cardioprotection against various heart diseases. However, its cardioprotective effects in DIC are still unknown. We hypothesized that donepezil reduces reactive oxygen species (ROS) production, mitochondrial dysfunction, mitochondrial dynamics imbalance, necroptosis, and apoptosis in DIC rats. Male Wistar rats were assigned to receive either normal saline solution (n = 8) or doxorubicin (3 mg/kg, 6 doses, n = 16) via intraperitoneal injection. The doxorubicin-treated rats were further subdivided to receive either sterile drinking water (n = 8) or donepezil (5 mg/kg/day, p.o., n = 8) for 30 days. At the end of the experiment, the left ventricular (LV) function was determined. Serum and heart tissue were collected to evaluate histological and biochemical parameters. Doxorubicin-treated rats exhibited higher levels of inflammatory cytokines and ROS production. Doxorubicin also impaired mitochondrial function, mitochondrial dynamics balance, mitophagy, and autophagy, which culminated in apoptosis. Furthermore, doxorubicin increased necroptosis as evidenced by increased phosphorylation of receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed-lineage kinase domain-like. All of these mechanisms led to LV dysfunction. Interestingly, donepezil alleviated mitochondrial injury, mitophagy, autophagy, and cardiomyocyte death, leading to improved LV function in DIC. In conclusion, donepezil attenuated DIC-induced LV dysfunction by reducing mitochondrial damage, mitophagy, autophagy, apoptosis, and necroptosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The cancer burden on health and socioeconomics remains exceedingly high, with more than ten million new cases reported worldwide in 2018. The financial cost of managing cancer patients has great economic impact on both an individual and societal levels. Currently, many chemotherapeutic agents are available to treat various malignancies. One of these agents is doxorubicin, which was isolated from Streptomyces peucetius in the 1960s. Doxorubicin is frequently administered in combination with other agents as a mainstay chemotherapeutic regimen in many settings, since there is well-documented evidence that it is effective in eliminating malignant cells. Doxorubicin exerts its anti-tumor properties through DNA intercalation and topoisomerase inhibition. It also contains a quinone moiety which is susceptible to redox reactions with certain intracellular molecules, thereby leading to the production of reactive oxygen species. The oxidative stress following doxorubicin exposure is responsible for its well-documented cardiotoxicity, impairing cardiac contractility, ultimately resulting in congestive heart failure. Despite the cumulative evidence noting its adverse effects on the heart, limited information is available regarding the mechanistic association between doxorubicin and cardiac arrhythmias. There is compelling evidence to suggest that doxorubicin also causes proarrhythmic effects. Several case reports and studies in cancer patients have attributed many arrhythmic events to doxorubicin, some of which are life-threatening such as complete heart block and ventricular fibrillation. In this review, reports regarding the potential arrhythmic complications associated with doxorubicin from previous studies investigating the effects of doxorubicin on cardiac electrophysiological properties are comprehensively summarized and discussed. Consistencies and controversial findings from in vitro, in vivo, ex vivo, and clinical studies are presented and mechanistic insights regarding the effects of doxorubicin are also discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)