Mechanisms of Cardiotoxicity of Cancer Chemotherapeutic Agents: Cardiomyopathy and Beyond

Abstract

Tremendous strides have been made in the treatment of various oncological diseases such that patients are surviving longer and are having better quality of life. However, the success has been tainted by the iatrogenic cardiac toxicities. This is especially concerning in the younger population who are facing cardiac disease such as heart failure in their 30s and 40s as the consequence of the anthracycline's side effects (used for childhood leukemia and lymphoma). This resulted in the awareness of cardiotoxic effects of anticancer drugs and emergence of a new discipline: oncocardiology. Since then, numerous anticancer drugs have been correlated to cardiomyopathy. Additionally, other cardiovascular effects have been identified, which includes but is not limited to myocardial infarction, thrombosis, hypertension, arrhythmias, and pulmonary hypertension. In this review we examine some of the anticancer agents that mitigate cardiotoxicity and present current knowledge of molecular mechanism(s). The aim of the review is to ignite awareness of emerging cardiotoxic effects as new generations of anticancer agents are being tested in clinical trials and introduced as part of the therapeutic armamentarium to our oncological patients.

Figure 1. Schematic representation of DOX/DNA/Top II Beta ternary Complex

Activation of the ternary complex results in double stranded DNA breaks which upregulates apoptotic signaling pathway. Furthermore, there is production of reactive oxygen species (ROS). Additionally, there is downregulation of peroxisome proliferation activated receptor gamma co-activator 1 alpha and beta (Ppargc-1 α/β) which results in mitochondrial dysfunction and decreased mitochondrial biogenesis. These pathways culminates into cardiotoxicity