Effects of doxorubicin on the heart: From molecular mechanisms to intervention strategies

Cancer remains a major public health problem worldwide and was responsible for 9.6 million deaths in 2018. Oncologic treatments such as doxorubicin (Dox) and trastuzumab (Trz) are chemotherapeutic drugs used to treat several types of cancer, including solid and non-solid malignancies. Although these drugs have a significant impact on the reduction in mortality of cancer patients, this treatment has an adverse effect on the cardiovascular system. The mechanisms associated with Dox-induced cardiotoxicity involve inflammation, oxidative stress, apoptosis, mitochondria impairment and dysregulation of autophagy. Unfortunately, Trz, an effective anti-cancer drug, can potentiate these adverse effects. Trz is a recombinant DNA-derived humanized monoclonal antibody against human epidermal growth factor receptor 2 (HER2). Despite its high anti-cancer efficacy, Trz also has a cardiotoxic effect. Unlike Dox, this adverse effect of Trz on the heart is mostly reversible. A strategy to prevent this undesirable effect is urgently needed. Currently, several pharmacological interventions have shown promising results that might effectively attenuate Dox- and Trz-induced cardiac dysfunction. In this review, reports from in vitro, in vivo and clinical studies pertinent to the underlying mechanisms involved in chemotherapy-induced cardiotoxicity, are comprehensively summarized and discussed. In addition, the potential pharmacological interventions to prevent these cardiotoxic effects are described.