Understanding Doxorubicin-induced cardiotoxicity

Abstract

Doxorubicin (DOX) is a highly effective anthracycline chemotherapeutic agent used to treat a wide range of cancers. However, its clinical use is significantly limited by the development of dose-dependent cardiotoxicity, manifesting as acute, early-onset, or late-onset chronic progressive cardiomyopathy, often leading to heart failure. Understanding the complex mechanisms underlying DOX-induced cardiotoxicity is crucial for developing effective preventative and treatment strategies. DOX's cardiotoxic effects are multifaceted, involving several interconnected pathways. A primary mechanism involves the generation of reactive oxygen species (ROS) through redox cycling of DOX's quinone moiety. This oxidative stress damages cellular components, including lipids, proteins, and DNA, leading to mitochondrial dysfunction and ultimately cardiomyocyte apoptosis. Iron plays a crucial role in this ROS generation, exacerbating oxidative damage. DOX also interferes with topoisomerase IIβ, an enzyme crucial for DNA replication and repair, leading to DNA damage and genomic instability in cardiomyocytes. Furthermore, DOX disrupts calcium homeostasis within cardiomyocytes, contributing to contractile dysfunction and cell death. Recent research has highlighted the role of endoplasmic reticulum stress, autophagy dysregulation, and immune system activation in DOX-induced cardiotoxicity. Beyond these cellular mechanisms, genetic predispositions and patient-specific factors, such as age, pre-existing cardiovascular disease, and concomitant medications, can influence the susceptibility to DOX-induced cardiotoxicity. Current research focuses on identifying biomarkers for early detection of cardiotoxicity and developing cardioprotective strategies. These strategies include the use of antioxidants, iron chelators, and targeted therapies aimed at mitigating ROS generation, preserving mitochondrial function, and inhibiting specific signaling pathways involved in DOX-induced cardiomyocyte damage. Further research is needed to fully elucidate the intricate mechanisms involved and develop effective clinical strategies to minimize the risk of this debilitating side effect, ultimately improving the quality of life for cancer survivors.