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J. Biol. Chem., Vol. 277, Issue 28, 25568-25575, July 12, 2002

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Activation of Caspase Pathways during Iron Chelator-mediated Apoptosis^*

Bryan T. Greene^§, Jackie Thorburn^§, Mark C. Willingham^§¶, Andrew Thorburn^§, Roy P. Planalp, Martin W. Brechbiel^**, Jamie Jennings-Gee^§, John Wilkinson IV^§, Frank M. Torti^§, and Suzy V. Torti^§§§

From the Departments of  Cancer Biology, ^¶ Pathology, and  Biochemistry and the ^§ Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, the  Department of Chemistry, University of New Hampshire, Durham, New Hampshire 03824, and the ^** Radiation Oncology Branch, National Institutes of Health, Bethesda, Maryland 20892

Iron chelators have traditionally been used in the treatment of iron overload. Recently, chelators have also been explored for their ability to limit oxidant damage in cardiovascular, neurologic, and inflammatory disease as well as to serve as anti-cancer agents. To determine the mechanism of cell death induced by iron chelators, we assessed the time course and pathways of caspase activation during apoptosis induced by iron chelators. We report that the chelator tachpyridine sequentially activates caspases 9, 3, and 8. These caspases were also activated by the structurally unrelated chelators dipyridyl and desferrioxamine. The critical role of caspase activation in cell death was supported by microinjection experiments demonstrating that p35, a broad spectrum caspase inhibitor, protected HeLa cells from chelator-induced cell death. Apoptosis mediated by tachpyridine was not prevented by blocking the CD95 death receptor pathway with a Fas-associated death domain protein (FADD) dominant-negative mutant. In contrast, chelator-mediated cell death was blocked in cells microinjected with Bcl-XL and completely inhibited in cells microinjected with a dominant-negative caspase 9 expression vector. Caspase activation was not observed in cells treated with N-methyl tachpyridine, an N-alkylated derivative of tachpyridine which lacks an ability to react with iron. These results suggest that activation of a mitochondrial caspase pathway is an important mechanism by which iron chelators induce cell death.

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