Topoisomerase IIβ-Mediated DNA double-strand breaks:: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane
Topoisomerase IIβ-Mediated DNA double-strand breaks:: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane
复制标题
DOI：
10.1158/0008-5472.can-07-1649
复制
发表时间：
2007-09-15
期刊：
影响因子：
11.2
通讯作者：
Liu, Leroy F.
中科院分区：
文献类型：
--
作者：
Lyu, Yi Lisa;Kerrigan, John E.;Liu, Leroy F.
阿霉素是临床上最有效、应用最广泛的抗癌药物之一。然而，心脏毒性是以阿霉素为基础的治疗的威胁生命的副作用之一。Dexrazoxane(Zinecard，也称为ICRF-187)已在临床上用作心脏保护剂，对抗阿霉素的心脏毒性。然而，阿霉素心脏毒性的分子基础和右氧氟沙星的心脏保护作用尚不完全清楚。在本研究中，我们发现右旋氮杂环己烷能特异性地阻断阿霉素诱导的H9C2心肌细胞DNA损伤信号GAMA-H_2AX，但不能阻断喜树碱或过氧化氢的作用。蛋白酶体抑制剂Bortezomib和MG132也能特异性地消除阿霉素引起的DNA损伤，并且与TOP2β(+/+)MEF相比，Top2β(-/-)小鼠胚胎成纤维细胞(MEF)的DNA损伤明显减少，这表明蛋白酶体和DNA拓扑异构酶IIβ(TOP2β)参与了这一过程。此外，Dexrazoxane除了拮抗TOP2裂解复合体的形成外，还能诱导TOP2β的快速降解，这与减少阿霉素诱导的DNA损伤是平行的。综上所述，我们的结果提示Dexrazoxane通过干扰TOP2β来拮抗阿霉素引起的DNA损伤，这可能意味着TOP2β参与了阿霉素的心脏毒性。蛋白酶体和TOP2β在阿霉素诱导的DNA损伤中的具体参与与蛋白酶体处理阿霉素诱导的TOP2β-DNA共价复合体暴露TOP2β隐藏的DNA双链断裂的模型一致。
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 top2 beta(-/-) mouse embryonic fibroblasts (MEF) compared with TOP2 beta(+/+) MEFs, suggesting the involvement of proteasome and DNA topoisomerase II beta (Top2 beta). Furthermore, in addition to antagonizing Top2 cleavage complex formation, dexrazoxane also induced rapid degradation of Top2 beta, which paralleled the reduction of doxorubicin-induced DNA damage. Together, our results suggest that dexrazoxane antagonizes doxorubicin-induced DNA damage through its interference with Top2 beta, which could implicate Top2 beta in doxorubicin cardiotoxicity. The specific involvement of proteasome and Top2 beta in doxorubicin-induced DNA damage is consistent with a model in which proteasomal processing of doxorubicin-induced Top2 beta-DNA covalent complexes exposes the Top2 beta-concealed DNA double-strand breaks.