Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection

Abstract

Chemotherapy and targeted therapies have significantly improved the prognosis of oncology patients. However, these antineoplastic treatments may also induce adverse cardiovascular effects, which may lead to acute or delayed onset of cardiac dysfunction. These common cardiovascular complications, commonly referred to as cardiotoxicity, not only may require the modification, suspension, or withdrawal of life-saving antineoplastic therapies, with the risk of reducing their efficacy, but can also strongly impact the quality of life and overall survival, regardless of the oncological prognosis. The onset of cardiotoxicity may depend on the class, dose, route, and duration of administration of anticancer drugs, as well as on individual risk factors. Importantly, the cardiotoxic side effects may be reversible, if cardiac function is restored upon discontinuation of the therapy, or irreversible, characterized by injury and loss of cardiac muscle cells. Subclinical myocardial dysfunction induced by anticancer therapies may also subsequently evolve in symptomatic congestive heart failure. Hence, there is an urgent need for cardioprotective therapies to reduce the clinical and subclinical cardiotoxicity onset and progression and to limit the acute or chronic manifestation of cardiac damages. In this review, we summarize the knowledge regarding the cellular and molecular mechanisms contributing to the onset of cardiotoxicity associated with common classes of chemotherapy and targeted therapy drugs. Furthermore, we describe and discuss current and potential strategies to cope with the cardiotoxic side effects as well as cardioprotective preventive approaches that may be useful to flank anticancer therapies.

Keywords: cardiomyocyte death; cardiomyocyte dysfunction; cardiomyocyte survival; cardioncology; cardioprotection; cardiotoxicity; chemotherapy; targeted therapy.

FIGURE 1

Cellular and molecular mechanisms of the cardiotoxic effects exerted by anthracyclines. Schematic diagram showing the impact of anthracyclines on a multitude of cardiomyocyte-intrinsic mechanisms leading to mitochondrial dysfunction and structural damage and/or DNA damage by topoisomerase activity, in turn leading to cardiomyocyte death and heart failure. Additional mechanisms of anthracycline-induced cardiotoxicity include deregulation of fibroblasts, endothelial, and immune cells, in turn concurring to cardiac remodeling.

FIGURE 2

Cellular and molecular mechanisms of the cardiotoxic effects exerted by fluoropyrimidines. Schematic diagram showing the impact of fluoropyrimidines on cardiac dysfunction due to myocardial ischemia induced by deregulation of vascular smooth muscle cells and erythrocytes. Additional mechanisms of taxane-induced cardiotoxicity include heart failure, consequent to cardiomyocyte death induced by cardiomyocyte-intrinsic mechanisms (increased ROS production) or myocardial infarction consequent to coronary artery thrombosis caused by endothelial cell senescence and death.

FIGURE 3

Cellular and molecular mechanisms of the cardiotoxic effects exerted by taxanes. Schematic diagram showing the main cardiotoxic effects of taxanes, namely atrial fibrillation and cardiac dysfunction, as a result of the disturbance of the conduction system or cardiomyocyte dysfunction, respectively.

FIGURE 4

Cellular and molecular mechanisms of the cardiotoxic effects exerted by alkylating drugs. Schematic diagram showing the impact of alkylating agents in promoting heart failure due to cardiomyocyte death consequent to myocardial infarction. Additional mechanisms of alkylating drug-induced cardiotoxicity include heart failure consequent to cardiomyocyte death induced by oxidative stress and cardiac remodeling following activation of pro-inflammatory pathways.

FIGURE 5

Cellular and molecular mechanisms of the cardiotoxic effect exerted by ERBB targeting monoclonal antibodies and tyrosine kinase inhibitors. Schematic diagram showing the impact of ERBB targeting therapies on cardiomyocyte dysfunction caused by the impairment of Neuregulin-1 signaling. However, in combination with anthracyclines, anti-HER2 monoclonal antibody trastuzumab may also induce heart failure as a consequence of cardiomyocyte death induced by ROS accumulation.

FIGURE 6

Cellular and molecular mechanisms of the cardiotoxic effects exerted by VEGFR/PDGFR and BCR-ABL and tyrosine kinase inhibitors. Schematic diagram showing the impact of VEGFR/PDGFR and BCR-ABL inhibition, resulting in a reversible cardiac disfunction. Anti-VEFGR activity impairs cardiac function by inducing capillary rarefaction consequent to reduced angiogenesis or hypertension derived from reduced NO production. Anti-PDGFR activity induces cardiac dysfunction by promoting the loss of pericytes, which in turn impairs the coronary vasculature. Anti-BCR-ABL inhibition may results in myocardial ischemia and cardiac dysfunction consequent to thrombotic microangiopathy.