ANTHRACYCLINE-INDUCED CARDIOTOXICITY: MECHANISM AND PREVENTION

Anthracyclines have been integral to cancer therapy for over 50 years, but their clinical use is constrained by dose-dependent cardiotoxicity. These agents target topoisomerase 2a, a critical enzyme for DNA replication, to exert their anticancer effects. Notably, while adult cardiomyocytes lack topoisomerase 2a, they do express topoisomerase 2b. Using genetic models, we demonstrated that deleting topoisomerase 2b in cardiomyocytes prevents anthracycline-induced DNA double-strand breaks, ROS production, mitochondrial dysfunction, and heart failure. These findings identify topoisomerase 2b as the key mediator of anthracycline-induced cardiotoxicity. Dexrazoxane, a Food and Drug Administration (FDA)-approved agent for preventing doxorubicin-induced cardiotoxicity, acts as a catalytic inhibitor of topoisomerases. However, this activity could potentially diminish doxorubicin's anticancer efficacy. New evidence, discovered serendipitously, shows that dexrazoxane selectively induces degradation of topoisomerase 2b without affecting topoisomerase 2a. A promising alternative approach involves pretreating with dexrazoxane prior to doxorubicin infusion. This strategy is supported by preclinical studies and is being tested in the PHOENIX trial.