Corna Gianfranca, Galy Bruno, Hentze Matthias W, Cairo Gaetano
Institute of General Pathology, University of Milan, Via Mangiagalli 31, Milan 20133, Italy.
J Mol Med (Berl). 2006 Jul;84(7):551-60. doi: 10.1007/s00109-006-0068-y. Epub 2006 Jun 13.
Iron aggravates the cardiotoxicity of doxorubicin (DOX), a widely used anticancer anthracycline. The amount of iron in the cell is regulated by the iron regulatory proteins (IRPs)-1 and -2 that control the posttranscriptional expression of key iron metabolism genes. In vitro and cell culture studies revealed the ability of DOX to modulate the activity of both IRPs. However, conflicting data were obtained from different cell types and experimental conditions. To investigate the connection between acute DOX cardiotoxicity and the IRPs in a mammalian organism, we analyzed IRP activity and the expression of IRP target genes in the heart of mice subjected to DOX treatment. DOX exposure elicits a differential modulation of the two IRPs with reduced IRP2 activity and unchanged IRP1 activity. IRP2 downmodulation is associated with the upregulation of the ferritin L and H genes and decreased expression of the transferrin receptor 1 (TfR1). To directly test the role of IRP1 in DOX cardiotoxicity, the DOX response was analyzed in mice lacking IRP1. DOX-mediated IRP2 downmodulation and regulation of ferritin and TfR1 expression is identical in Irp1 (-/-) mice compared to wild type, as is the degree of oxidative damage of the heart assessed by thioredoxin and thiobarbituric acid reactive substance levels and by brain natriuretic peptide mRNA expression. These data demonstrate that the alterations of cardiac iron homeostasis related to acute anthracycline cardiotoxicity occur independently of IRP1. The observed IRP2 downmodulation could serve as a means to counteract DOX cardiotoxicity by reducing the "free" cellular iron pool.
铁会加剧阿霉素（DOX）的心脏毒性，阿霉素是一种广泛使用的抗癌蒽环类药物。细胞内铁的含量由铁调节蛋白（IRPs）-1和-2调控，它们控制着关键铁代谢基因的转录后表达。体外和细胞培养研究揭示了DOX调节两种IRPs活性的能力。然而，在不同细胞类型和实验条件下获得的数据相互矛盾。为了研究急性DOX心脏毒性与哺乳动物机体中IRPs之间的联系，我们分析了接受DOX治疗的小鼠心脏中IRP活性和IRP靶基因的表达。DOX暴露引起两种IRPs的差异调节，IRP2活性降低而IRP1活性不变。IRP2下调与铁蛋白L和H基因的上调以及转铁蛋白受体1（TfR1）的表达降低有关。为了直接测试IRP1在DOX心脏毒性中的作用，我们分析了缺乏IRP1的小鼠对DOX的反应。与野生型相比，Irp1（-/-）小鼠中DOX介导的IRP2下调以及铁蛋白和TfR1表达的调节是相同的，通过硫氧还蛋白和硫代巴比妥酸反应性物质水平以及脑钠肽mRNA表达评估的心脏氧化损伤程度也是相同的。这些数据表明，与急性蒽环类药物心脏毒性相关的心脏铁稳态改变独立于IRP1发生。观察到的IRP2下调可能是通过减少细胞“游离”铁池来对抗DOX心脏毒性的一种方式。
