Lyu Yi Lisa, Kerrigan John E, Lin Chao-Po, Azarova Anna M, Tsai Yuan-Chin, Ban Yi, Liu Leroy F
Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635, USA.
Cancer Res. 2007 Sep 15;67(18):8839-46. doi: 10.1158/0008-5472.CAN-07-1649.
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.
阿霉素是临床上最有效且使用最广泛的抗癌药物之一。然而，心脏毒性是基于阿霉素治疗的危及生命的副作用之一。右丙亚胺（Zinecard，也称为ICRF-187）已在临床上用作预防阿霉素心脏毒性的心脏保护剂。然而，阿霉素心脏毒性的分子基础以及右丙亚胺的心脏保护作用尚未完全明确。在本研究中，我们发现右丙亚胺能特异性消除阿霉素在H9C2心肌细胞中诱导的DNA损伤信号γ-H2AX，但对喜树碱或过氧化氢诱导的该信号无此作用。蛋白酶体抑制剂硼替佐米和MG132也能特异性消除阿霉素诱导的DNA损伤，并且与野生型TOP2β(+/+)小鼠胚胎成纤维细胞（MEF）相比，在top2β(-/-)小鼠胚胎成纤维细胞中阿霉素诱导的DNA损伤显著减少，这表明蛋白酶体和DNA拓扑异构酶IIβ（Top2β）参与其中。此外，除了拮抗Top2切割复合物的形成，右丙亚胺还能诱导Top2β快速降解，这与阿霉素诱导的DNA损伤减少相平行。总之，我们的结果表明右丙亚胺通过干扰Top2β来拮抗阿霉素诱导的DNA损伤，这可能意味着Top2β与阿霉素心脏毒性有关。蛋白酶体和Top2β在阿霉素诱导的DNA损伤中的特异性参与与一种模型一致，即在该模型中，蛋白酶体对阿霉素诱导的Top2β-DNA共价复合物的加工暴露了Top2β隐藏的DNA双链断裂。
