Oxidant-Induced Iron Signaling in Doxorubicin-Mediated Apoptosis

Abstract

Publisher Summary This chapter discusses the methodological aspects linking Doxorubicin (DOX)-induced intracellular oxidative stress, iron signaling, and apoptosis. Pertinent redox parameters measured are the following: intracellular glutathione (GSH) levels, aconitase activity, IRP–IRE interaction, transferrin receptor (TfR) expression, cellular iron uptake, DCFH oxidation to DCF, and apoptosis. DOX or adriamycin, a quinone-containing anthracycline antibiotic, is a widely used chemotherapeutic drug for treating leukemia, breast cancer, Hodgkin's disease, or sarcomas. The clinical efficacy of this drug is greatly restricted because of the development of a severe form of cardiomyopathy or congestive heart failure in cancer patients treated with this drug. Current evidence indicates that DOX-mediated cardiotoxicity may be caused by increased generation of reactive oxygen species (ROS) such as superoxide, hydrogen peroxide (H2O2), or hydroxyl radicals (·OH) through redox-activation of DOX. The proapoptotic effect of DOX in myocytes and endothelial cells is attributed to intracellular iron and H2O2 formation. Recently, it is showed that intracellular iron plays a critical role in initiating oxidant-induced apoptosis through upregulation of TfR. Transferrin receptor synthesis is regulated by interaction of the iron regulatory protein (IRP) with the iron-responsive element (IRE) present on the 30-untranslated region of TfR mRNA. The oxidant-induced iron signaling mechanism is a new perspective that should be more fully explored in DOX cardiotoxicity.