Dexrazoxane averts idarubicin-evoked genomic damage by regulating gene expression profiling associated with the DNA damage-signaling pathway in BALB/c mice

Abstract

Idarubicin is an anthracycline antileukemic agent widely used in the treatment of hematological malignancies. However, cardiotoxicity and secondary leukemia have been reported after idarubicin treatment. Dexrazoxane is the only medication approved by FDA to prevent anthracycline-evoked cardiotoxicity. However, lack of information on the genomic damage caused by the combination of these 2 drugs prompted us to conduct the current study. We treated mice with different doses of idarubicin and/or dexrazoxane. Genomic DNA damage, apoptosis, and reactive oxygen species (ROS) were evaluated in the bone marrow cells. Our results demonstrate that mice pretreated of with dexrazoxane had significant lower genomic damage, apoptosis and ROS generation compared with that of mice treated with idarubicin alone, an effect that was dependent on dexrazoxane dose. The expression of 84 genes implicated in DNA damage-signaling pathways was quantified using an RT2Profiler PCR Array. Idarubicin treatments altered the expression of 58 genes, and 16 of those were expressed at significantly different level. In treatments combining idarubicin and dexrazoxane, substantial restorations of mRNA expression of these genes were observed. RT-qPCR was performed for selected genes and the alteration of these genes was confirmed. Alterations in mRNA expression of a subset of genes were further proved by Western blotting analysis of protein levels, which nearly showed similar alterations. Conclusively, dexrazoxane can be safely co-administered with idarubicin. Moreover, dexrazoxane minimizes idarubicin-evoked genomic damage via its radical scavenging and DNA repairenhancing activities. Thus, dexrazoxane may help avert secondary malignancies in cancer patients in remission who are exposed to idarubicin.