Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms and Strategies for Cardioprotection

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.