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

Abstract

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.

Myocardial Protection During Cardiotoxic Chemotherapy

“…However, multiple clinical trials with different drugs using this strategy have been negative, 58 probably because these drugs do not prevent DNA double-strand breaks and activation of p53. 59 Dexrazoxane has traditionally been thought to protect the heart from doxorubicin-associated damage by binding free iron and removing iron from the doxorubicin-iron complex, preventing the formation of oxygen radicals. Because dexrazoxane also forms a tight complex with the ATPase domain of topoisomerase 2, the most important mechanism for its cardiopreventive effects is likely to be preventing anthracyclines from binding to the topoisomerase 2β-DNA complex by trapping topoisomerase 2β in a closed-clamp form.…”

Dexrazoxane exacerbates doxorubicin-induced testicular toxicity

“…The high efficacy of DXR chemotherapy is conferred to abundant expression of TopoIIa in cancer cells. TopoIIb, but not TopoIIa, is expressed in adult heart (Lyu et al 2007, Vejpongsa & Yeh 2014. TopoIIb has been implicated in the mechanism that underlies DXRinduced cardiotoxicity where it targets TopoIIb in both nuclei and mitochondria of cardiomyocytes.…”

Cardio-Oncology

“…18 Recent data suggest an alternative mechanism, where dexrazoxane binding to Top2β leads to Top2β degradation. 19 Dexrazoxane is not broadly used to prevent AIC, in part because of the concerns of diminished antitumor effects, as well as a role in promoting secondary malignancy. Perhaps, the new insights into dexrazoxane's effects on Top2β as a mechanism for prevention of AIC will lead to a re-examination of its clinical utility.…”