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 RT2 Profiler 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 repair-enhancing activities. Thus, dexrazoxane may help avert secondary malignancies in cancer patients in remission who are exposed to idarubicin.
Subject(s)
Antibiotics, Antineoplastic/toxicity , Antioxidants/pharmacology , Bone Marrow Cells/drug effects , DNA Damage/drug effects , Dexrazoxane/pharmacology , Idarubicin/toxicity , Signal Transduction/drug effects , Transcriptome , Animals , Apoptosis/drug effects , Blotting, Western , Bone Marrow Cells/metabolism , Bone Marrow Cells/pathology , Comet Assay , DNA Repair/drug effects , Dose-Response Relationship, Drug , Gene Expression Profiling/methods , Gene Expression Regulation , Mice, Inbred BALB C , Micronucleus Tests , Oxidative Stress/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reactive Oxygen Species/metabolismABSTRACT
In order to study the mechanisms underlying the alleviation of aflatoxin B1-induced genomic damage by proanthocyanidins (PAs), we examined the modulation of oxidative DNA damage induced by aflatoxin B1 in PAs-pretreated animals. The effects of PAs on changes in the expression of DNA damage and repair genes induced by aflatoxin B1 were also evaluated in rat marrow cells. Administration of PAs before aflatoxin B1 significantly mitigated aflatoxin B1-induced oxidative DNA damage in a dose-dependent manner. Aflatoxin B1 treatment induced significant alterations in the expression of specific DNA repair genes, and the pre-treatment of rats with PAs ameliorated the altered expression of these genes. Conclusively, PAs protect against aflatoxin B1-induced oxidative DNA damage in rats. These protective effects are attributed to the antioxidant effects of PA and enhanced DNA repair through modulation of DNA repair gene expression. Therefore, PAs are a promising chemoprotective agent for averting genotoxic risks associated with aflatoxin B1 exposure.
