Anthracycline compounds are major culprits in chemotherapy-induced cardiotoxicity, which is the chief limiting factor in delivering optimal chemotherapy to cancer patients. Although extensive efforts have been devoted to identifying strategies to prevent anthracycline-induced cardiotoxicity, there is little consensus regarding the best approach. Recent advances in basic mechanisms of anthracycline-induced cardiotoxicity provided a unified theory to explain the old reactive-oxygen species hypothesis and identified topoisomerase 2β as the primary molecular target for cardioprotection. This review outlines current strategies for primary and secondary prevention of anthracycline-induced cardiotoxicity resulting from newly recognized molecular mechanisms and identifies knowledge gaps requiring further investigation.

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 2β (Top2β) 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 Top2β 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, Top2α-specific anthracyclines should be tested to determine whether they will spare the heart. Second, Top2β should be studied as a potential biomarker to predict risk of developing cardiotoxicity before anthracycline treatment. Third, inhibiting and deleting Top2β in the heart should also be tested as primary prevention strategies. We propose that Top2β is a promising molecular target that can be used to design interventions to prevent anthracycline-induced cardiotoxicity.

The cardiovascular care of cancer patients (“Cardio-Oncology”) has emerged as a new discipline in clinical medicine given recent advances in cancer therapy, and is driven by the cardiovascular complications that occur as a direct result of cancer therapy. Traditional therapies, such as anthracyclines and radiation, have been recognized for years to have cardiovascular complications. Less expected were the cardiovascular effects of “targeted” cancer therapies, which were initially felt to be specific to cancer cells and would spare any adverse effects on the heart. Cancers are typically driven by mutations, translocations, and/or over-expression of protein kinases. The majority of these mutated kinases are tyrosine kinases, though serine/threonine kinases also play key roles in some malignancies. Several agents were developed to target these kinases, but many more are in development. Major successes have been largely restricted to agents targeting Her2 (mutated or over-expressed in breast cancer), BCR-ABL (CML and some cases of ALL),and c-Kit (gastrointestinal stromal tumor).Other agents targeting more complex malignancies such as advanced solid tumors have had successes, but have not extended life to the degree seen with CML. Years before the first targeted therapeutic, Judah Folkman correctly proposed that to address solid tumors, one had to target the inherent neo-angiogenesis. Unfortunately, emerging evidence confirms that angiogenesis inhibitors cause cardiac complications, including hypertension, thrombosis, and heart failure. And therein lies the Catch 22. On the other hand, cardiomyopathies that arise unexpectedly from such targeted therapies can provide key insights into the normal function of the heart.