Topoisomerase 2 beta: A Promising Molecular Target for Primary Prevention of Anthracycline-Induced Cardiotoxicity

Anthracyclines are powerful chemotherapy agents that are still widely used today. However, their clinical use is limited by the development of dose-dependent cardiotoxicity. Recently, we showed that topoisomerase 2 beta (Top2 beta) is required for anthracycline to induce DNA double-strand breaks and changes in the transcriptome, leading to mitochondrial dysfunction and generation of reactive oxygen species. Furthermore, deleting Top2 beta from cardiomyocytes prevented the development of anthracycline-induced cardiotoxicity in mice. On the basis of this molecular insight, new strategies should be developed to prevent anthracycline-induced cardiotoxicity. First, Top2 alpha-specific anthracyclines should be tested to determine whether they will spare the heart. Second, Top2 beta should be studied as a potential biomarker to predict risk of developing cardiotoxicity before anthracycline treatment. Third, inhibiting and deleting Top2 beta in the heart should also be tested as primary prevention strategies. We propose that Top2 beta is a promising molecular target that can be used to design interventions to prevent anthracycline-induced cardiotoxicity.