From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview

Abstract

Antineoplastic therapies have significantly improved the prognosis of oncology patients. However, these treatments can bring to a higher incidence of side-effects, including the worrying cardiovascular toxicity (CTX). Substantial evidence indicates multiple mechanisms of CTX, with redox mechanisms playing a key role. Recent data singled out mitochondria as key targets for antineoplastic drug-induced CTX; understanding the underlying mechanisms is, therefore, crucial for effective cardioprotection, without compromising the efficacy of anti-cancer treatments. CTX can occur within a few days or many years after treatment. Type I CTX is associated with irreversible cardiac cell injury, and it is typically caused by anthracyclines and traditional chemotherapeutics. Type II CTX is generally caused by novel biologics and more targeted drugs, and it is associated with reversible myocardial dysfunction. Therefore, patients undergoing anti-cancer treatments should be closely monitored, and patients at risk of CTX should be identified before beginning treatment to reduce CTX-related morbidity. Genetic profiling of clinical risk factors and an integrated approach using molecular, imaging, and clinical data may allow the recognition of patients who are at a high risk of developing chemotherapy-related CTX, and it may suggest methodologies to limit damage in a wider range of patients. The involvement of redox mechanisms in cancer biology and anticancer treatments is a very active field of research. Further investigations will be necessary to uncover the hallmarks of cancer from a redox perspective and to develop more efficacious antineoplastic therapies that also spare the cardiovascular system. Antioxid. Redox Signal. 00, 000-000.

Comprehensive review of cardiovascular toxicity of drugs and related agents

“…Modern anticancer drugs have significantly contributed to the striking improvement in survival in many types of malignant neoplasm. Unfortunately, besides the typical adverse effects of anticancer drugs (e.g., nausea, vomiting, myelosuppression), several of these drugs may severely affect the heart with potentially life‐threatening consequences . Numerous detrimental effects to the heart may happen, including morphological alterations resulting in cardiomyopathy and/or changes in cardiac function (dysrhythmias or systolic/diastolic dysfunction).…”

“…Numerous detrimental effects to the heart may happen, including morphological alterations resulting in cardiomyopathy and/or changes in cardiac function (dysrhythmias or systolic/diastolic dysfunction). Clinically, heart failure/left ventricular dysfunction ranks among the most important cardiotoxic effects of some anticancer drugs . Other cardiotoxic effects of anticancer drugs are discussed only briefly.…”

“…Despite many experimental and clinical studies performed throughout past 40 years, the molecular basis for ANT‐induced cardiotoxicity remains elusive and is still a matter of debate and controversy . The prevailing mechanistic explanation centers around ANT‐induced and iron‐catalyzed formation of ROS, resulting in direct oxidative damage to the myocardium .…”

“…The prevailing mechanistic explanation centers around ANT‐induced and iron‐catalyzed formation of ROS, resulting in direct oxidative damage to the myocardium . Other hypotheses point to ANT‐induced impairment of mitochondrial bioenergetics, damage to mitochondrial DNA with subsequent perturbations in the expression of mitochondrial DNA‐encoded proteins, disruption of mitochondrial and cellular Ca 2+ homeostasis, and alterations in the expression and stability of cardiac myofilaments . Recently, a new and particularly interesting concept of ANT cardiotoxicity emerged when Yeh et al.…”

“…Effective management of established ANT cardiotoxicity is difficult and relies largely on pharmacological intervention with ACE inhibitors and β‐adrenergic blockers to control heart failure symptoms . Hence, there is a great emphasis to prevent the onset of cardiotoxicity.…”