title: Novel Polypyridyl chelators deplete cellular zinc and destabilize the X-linked inhibitor of apoptosis protein (XIAP) prior to induction of apoptosis in human prostate and breast cancer cells.
abstract: 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 (Zn)-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 Zn-chelators with different Zn 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 Zn-chelators N4Py and BnTPEN. Addition of Zn has a full protective effect on the cells treated with these chelators, while iron (Fe) addition has only partial protection that, however, can be further increased to a comparable level of protection as Zn by inhibition of ROS generation, indicating that cell death effects mediated by Fe- but not Zn-complexes involve redox cycling. These findings suggest that strong Zn-chelating agents may be useful in the treatment of apoptosis-resistant human cancers.
authors.affiliation: Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Departments of Oncology, Pharmacology and Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zuo
authors.forename: Sara M
authors.initials: SM
authors.lastname: Schmitt
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Fan
authors.forename: Caifeng
authors.initials: C
authors.lastname: Bi
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Kodanko
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; C431844:N4Py compound; D011725:Pyridines; D051636:X-Linked Inhibitor of Apoptosis Protein; D015032:Zinc