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Papers In Press, published online ahead of print April 29, 2002
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, N.C. 27157
Corresponding Author: storti{at}wfubmc.edu
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 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 that 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.
J. Biol. Chem, 10.1074/jbc.M110345200
Submitted on October 26, 2001
Revised on April 29, 2002
Accepted on April 29, 2002
Activation of caspase pathways during iron chelator-mediated apoptosis
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