Topoisomerase IIβ-mediated DNA double-strand breaks: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane

Lisa Lyu Yi, John E. Kerrigan, Chao Po Lin, Anna M. Azarova, Yuan Chin Tsai, Yi Ban, Leroy F. Liu

研究成果: 雜誌貢獻文章同行評審

424 引文 斯高帕斯(Scopus)

摘要

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 γ-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 top2β-/- mouse embryonic fibroblasts (MEF) compared with TOP2β+/+ MEFs, suggesting the involvement of proteasome and DNA topoisomerase IIβ (Top2β). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2β, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2β, which could implicate Top2β in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2β in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2β-DNA covalent complexes exposes the Top2β-concealed DNA double-strand breaks.
原文英語
頁(從 - 到)8839-8846
頁數8
期刊Cancer Research
67
發行號18
DOIs
出版狀態已發佈 - 9月 15 2007
對外發佈

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

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