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J. Biol. Chem., Vol. 277, Issue 19, 17179-17187, May 10, 2002

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Transferrin Receptor-dependent Iron Uptake Is Responsible for Doxorubicin-mediated Apoptosis in Endothelial Cells
ROLE OF OXIDANT-INDUCED IRON SIGNALING IN APOPTOSIS^*

Srigiridhar Kotamraju, Christopher R. Chitambar^§, Shasi V. Kalivendi, Joy Joseph, and B. Kalyanaraman^¶

From the  Biophysics Research Institute and Free Radical Research Center and the ^§ Division of Neoplastic Diseases, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

In the past, investigators have successfully used iron chelators to mitigate the cardiotoxicity of doxorubicin (DOX), a widely used anticancer drug that induces reactive oxygen species (ROS), oxidative damage, and apoptosis. Although intracellular iron plays a critical role in initiating DOX-induced apoptosis, the molecular mechanism(s) that link iron, ROS, and apoptosis are still unknown. In this study, we demonstrate that apoptosis results from the exposure of bovine aortic endothelial cells to DOX and that the apoptotic cell death is accompanied by a significant increase in cellular iron (⁵⁵Fe) uptake and activation of iron regulatory protein-1. Furthermore, DOX-induced iron uptake was shown to be mediated by the transferrin receptor (TfR)-dependent mechanism. Treatment with the anti-TfR antibody (IgA class) dramatically inhibited DOX-induced apoptosis, iron uptake, and intracellular oxidant formation as measured by fluorescence using dichlorodihydrofluorescein. Treatment with cell-permeable iron chelators and ROS scavengers inhibited DOX-induced cellular ⁵⁵Fe uptake, ROS formation, and apoptosis. Based on these findings, we conclude that DOX-induced iron signaling is regulated by the cell surface TfR expression, intracellular oxidant levels, and iron regulatory proteins. The implications of TfR-dependent iron transport in oxidant-induced apoptosis in endothelial cells are discussed.

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