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Topoisomerase IIß–Mediated DNA Double-Strand Breaks: Implications in Doxorubicin Cardiotoxicity and Prevention by Dexrazoxane

Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey

Requests for reprints: Yi Lisa Lyu and Leroy F. Liu, Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635. Phone: 732-235-4592; E-mail: lyuyi{at}umdnj.edu and lliu{at}umdnj.edu.

Doxorubicin is among the most effective and widely used anticancer drugs in the clinic. However, cardiotoxicity is one of the life-threatening side effects of doxorubicin-based therapy. Dexrazoxane (Zinecard, also known as ICRF-187) has been used in the clinic as a cardioprotectant against doxorubicin cardiotoxicity. The molecular basis for doxorubicin cardiotoxicity and the cardioprotective effect of dexrazoxane, however, is not fully understood. In the present study, we showed that dexrazoxane specifically abolished the DNA damage signal -H2AX induced by doxorubicin, but not camptothecin or hydrogen peroxide, in H9C2 cardiomyocytes. Doxorubicin-induced DNA damage was also specifically abolished by the proteasome inhibitors bortezomib and MG132 and much reduced in top2ß^–/– mouse embryonic fibroblasts (MEF) compared with TOP2ß^+/+ MEFs, suggesting the involvement of proteasome and DNA topoisomerase IIß (Top2ß). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2ß, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2ß, which could implicate Top2ß in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2ß in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2ß-DNA covalent complexes exposes the Top2ß-concealed DNA double-strand breaks. [Cancer Res 2007;67(18):8839–46]

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