Role of Oxidative Stress in the Mechanisms of Anthracycline-Induced Cardiotoxicity: Effects of Preventive Strategies

Abstract

Anthracycline-induced cardiotoxicity (AIC) persists as a significant cause of morbidity and mortality in cancer survivors. Although many protective strategies have been evaluated, cardiotoxicity remains an ongoing threat. The mechanisms of AIC remain unclear; however, several pathways have been proposed, suggesting a multifactorial origin. When the central role of topoisomerase 2β in the pathophysiology of AIC was described some years ago, the classical reactive oxygen species (ROS) hypothesis shifted to a secondary position. However, new insights have reemphasized the importance of the role of oxidative stress-mediated signaling as a common pathway and a critical modulator of the different mechanisms involved in AIC. A better understanding of the mechanisms of cardiotoxicity is crucial for the development of treatment strategies. It has been suggested that the available therapeutic interventions for AIC could act on the modulation of oxidative balance, leading to a reduction in oxidative stress injury. These indirect antioxidant effects make them an option for the primary prevention of AIC. In this review, our objective is to provide an update of the accumulated knowledge on the role of oxidative stress in AIC and the modulation of the redox balance by potential preventive strategies.

Figure 1

Mechanisms of anthracycline-induced cardiotoxicity and the role of oxidative stress. DOX: doxorubicin; GSH-Px: glutathione peroxidase; MPO: myeloperoxidase; PGC1 α/β: peroxisome proliferator-activated receptor-γ coactivator 1-α and 1-β; Rac1: a subunit of NADPH oxidase; ROS: reactive oxygen species; SOD: superoxide dismutase.

Figure 2

Potential cardioprotective therapies for anthracycline-induced cardiotoxicity. ACE: angiotensin-converting enzyme; CBR3: carbonyl reductase 3; DHA: docosahexaenoic acid; DNA DSBs: indicates deoxyribonucleic acid double-stranded breaks; EPA: eicosapentaenoic acid; GPx: glutathione peroxidase; MnSOD: Mn-superoxide dismutase; MPO: myeloperoxidase; n-3 PUFAs: n-3 polyunsaturated fatty acids; Nrf2: nuclear factor erythroid 2-related factor 2; PGC1 α/β: peroxisome proliferator-activated receptor-γ coactivator 1-α, and 1-β; PTP: permeability transition pores; Rac1: a subunit of NADPH oxidase; ROS: reactive oxygen species; Top2β: topoisomerase 2β; UCP2: mitochondrial uncoupling protein 2.