Epigenetic Changes Associated With Anthracycline‐Induced Cardiotoxicity

Abstract

Advances in cancer treatment have significantly improved the survival of patients with cancer, but, unfortunately, many of these treatments also have long‐term complications. Cancer treatment‐related cardiotoxicities are becoming a significant clinical problem that a new discipline, Cardio‐Oncology, was established to advance the cardiovascular care of patients with growing cancer populations. Anthracyclines are a class of chemotherapeutic agents used to treat many cancers in adults and children. Their clinical use is limited by anthracycline‐induced cardiotoxicity (AIC), which can lead to heart failure. Early‐onset cardiotoxicity appears within a year of treatment, whereas late‐onset cardiotoxicity occurs > 1 year and even up to decades after treatment completion. The pathophysiology of AIC was hypothesized to be caused by generation of reactive oxygen species that lead to lipid peroxidation, defective mitochondrial biogenesis, and DNA damage of the cardiomyocytes. The accumulation of anthracycline metabolites was also proposed to cause mitochondrial damage and the induction of cardiac cell apoptosis, which induces arrhythmias, contractile dysfunction, and cardiomyocyte death. This paper will provide a general overview of cardiotoxicity focusing on the effect of anthracyclines and their epigenetic molecular mechanisms on cardiotoxicity.

Impact of novel microbial secondary metabolites on the pharma industry

“…Several new anthracyclines are currently in clinical trials against prostate cancer and leukemia (Bigagli et al 2018 ; Tantawy et al 2020 ).…”

Molecular biomarkers in cardio‐oncology: Where we stand and where we are heading

“…In particular, epigenetics drive variations in gene expression and, subsequently, alter drug absorption, metabolism and excretion by regulating the expression of specific drugmetabolizing enzymes. [60,61] Furthermore, the advent of patient-specific hiPSC technology gives the opportunity to validate causal variants and elucidate new mechanisms of cardiotoxicity, thus reshaping our strategy in this field (Figure 4). [62] In respect with pharmacogenomics research in cardiooncology, hiPSCs offer two advantages: 1) they are a renewable source of multiple cardiovascular cell types and 2) they are genetically identical to the patients from whom they are derived.…”

“…In particular, epigenetics drive variations in gene expression and, subsequently, alter drug absorption, metabolism and excretion by regulating the expression of specific drug‐metabolizing enzymes. [ 60,61 ]…”

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

“…Mitochondrial toxicants are compounds that interrupt normal mitochondrial functions, resulting in compromised mitochondrial homeostasis, including disruption of oxidative phosphorylation, permeability transition, and generation of mitochondrial oxidative stress, contributing to energy supply disorder, aberrant intracellular signaling, toxic substances accumulation, autophagy or mitophagy disturbances, and programmed cell death, ultimately decreasing cardiac function [ 22 , 23 , 24 , 25 ]. At the organ level, many cardiac abnormalities are induced via these mechanisms, including cardiomyopathy [ 26 , 27 , 28 ], coronary heart disease [ 29 , 30 ], arrhythmias [ 31 , 32 ], ischemia reperfusion [ 33 , 34 ], and heart failure [ 35 , 36 ]. Mitochondrial impairment can adversely impact cardiomyocyte electrical excitability through mitochondrial gene expression alteration [ 37 ], mitochondrial membrane potential (MMP) collapse [ 38 ], excessive ROS generation [ 39 ], and ATP depletion [ 40 ], resulting in cardiac arrhythmias [ 41 , 42 ].…”