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 gamma-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 top2beta(-/-) mouse embryonic fibroblasts (MEF) compared with 
TOP2beta(+/+) MEFs, suggesting the involvement of proteasome and DNA 
topoisomerase IIbeta (Top2beta). Furthermore, in addition to antagonizing Top2 
cleavage complex formation, dexrazoxane also induced rapid degradation of 
Top2beta, which paralleled the reduction of doxorubicin-induced DNA damage. 
Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced 
DNA damage through its interference with Top2beta, which could implicate 
Top2beta in doxorubicin cardiotoxicity. The specific involvement of proteasome 
and Top2beta in doxorubicin-induced DNA damage is consistent with a model in 
which proteasomal processing of doxorubicin-induced Top2beta-DNA covalent 
complexes exposes the Top2beta-concealed DNA double-strand breaks.