Publication Date:
2012-04-16
Description:
X-linked inhibitor of apoptosis protein, XIAP, inhibits the initiation and execution phases of the apoptotic pathway. XIAP is the most potent member of the inhibitor of apoptosis protein (IAP) family of the endogenous caspase inhibitors. Therefore, targeting XIAP may be a promising strategy for the treatment of apoptosis-resistant malignancies. In this study we systematically studied the relationships of chemical structures of several novel ligands to their zinc-binding ability, molecular target XIAP, and tumor cell death-inducing activity. We show that treatment of PC-3 prostate cancer and MDA-MB-231 breast cancer cells with these membrane-permeable zinc-chelators with different zinc affinities results in varying degrees of XIAP depletion. Following decreased level of XIAP expression, we also show apoptosis-related caspase activation and cellular morphological changes upon treatment with strong zinc-chelators N4Py and BnTPEN. Addition of zinc has a full protective effect on the cells treated with these chelators, while iron addition has only partial protection that, however, can be further increased to a comparable level of protection as zinc by inhibition of ROS generation, indicating that cell death effects mediated by iron- but not zinc-complexes involve redox cycling. These findings suggest that strong zinc-chelating agents may be useful in the treatment of apoptosis-resistant human cancers. J. Cell. Biochem. © 2012 Wiley Periodicals, Inc.
Electronic ISSN:
0091-7419
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
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