A COMPREHENSIVE REVIEW OF THE MECHANISMS OF ACTION AND CARDIOTOXICITY OF DOXORUBICIN

Doxorubicin (DOX), an anthracycline antibiotic, is a chemotherapeutic agent used to treat various cancers, including breast cancer, leukemia, and lymphomas. Primary mechanisms of action are DNA intercalation and topoisomerase II inhibition to disrupt DNA replication and transcription, inducing apoptosis in rapidly dividing cancer cells. Its clinical utility is significantly limited by dose-dependent cardiotoxicity, driven by the generation of reactive oxygen species (ROS), mitochondrial damage, and inflammatory cytokine activation, often leading to irreversible heart failure. This review highlights recent insights into doxorubicin’s mechanisms of action and toxicity,
emphasising pathways such as mitochondrial dysfunction and apoptotic signalling in cardiomyocytes. Advanced delivery systems, including liposomal formulations and nanoparticle-based platforms, are explored for their ability to enhance tumor targeting while minimising exposure to healthy tissues. Notably, pH-sensitive and stimuli-responsive nanoparticles offer improved specificity, reducing systemic toxicity. Emerging strategies such as biomarker-guided therapy and pharmacogenomics enable early detection of cardiotoxicity and personalised dosing regimens. Predictive modelling using cardiac biomarkers and genetic profiling hold promising for identifying high-risk patients. Combination therapies, particularly with immune checkpoint inhibitors, provide opportunities to enhance efficacy while reducing doxorubicin doses and associated toxicities. Future advancements in precision medicine, green chemistry, targeted delivery system approaches are expected to mitigate doxorubicin’s cardiotoxic effects, broadening its clinical applicability and improving patient outcomes.