Signaling pathways underlying anthracycline cardiotoxicity

Significance: The cardiac side effects of hematological treatments are a major issue of the growing population of cancer survivors, often affecting patient survival even more than the tumor for which the treatment was initially prescribed. Among the most cardiotoxic drugs are anthracyclines (ANTs), highly potent antitumor agents, which still represent a mainstay in the treatment of hematological and solid tumors. Unfortunately, diagnosis, prevention, and treatment of cardiotoxicity are still unmet clinical needs, which call for a better understanding of the molecular mechanism behind the pathology. Recent Advances: This review article will discuss recent findings on the pathomechanisms underlying the cardiotoxicity of ANTs, spanning from DNA and mitochondrial damage to calcium homeostasis, autophagy, and apoptosis. Special emphasis will be given to the role of reactive oxygen species and their interplay with major signaling pathways. Critical Issues: Although new promising therapeutic targets and new drugs have started to be identified, their efficacy has been mainly proven in preclinical studies and requires clinical validation. Future Directions: Future studies are awaited to confirm the relevance of recently uncovered targets, as well as to identify new druggable pathways, in more clinically relevant models, including, for example, human induced pluripotent stem cell-derived cardiomyocytes.