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The molecular interaction of a copper chelate with human P-glycoprotein

The molecular interaction of a copper chelate with human P-glycoprotein One of the major reasons for multidrug resistance (MDR) in cancer is the overexpression of P-glycoprotein (P-gp, ABCB1), a drug efflux pump. A novel copper complex, namely, copper (II) N-(2-hydroxyacetophenone) glycinate (CuNG) previously synthesized and characterized by the authors had been tested in this study. In a cell-based assay system with human MDR1 cDNA overexpressed mouse fibroblast NIH MDR1-G185 cell line, we demonstrated that this metal complex can directly interact with this transporter. As CuNG increased cellular accumulation of doxorubicin in P-gp-expressing cells, we presumed that of CuNG may be potential to reverse P-gp-mediated drug resistance probably by lowering the P-gp expression at the protein as well as mRNA level. Interestingly, our studies on UIC2 (a conformation sensitive monoclonal antibody) binding assay indicated the direct interaction of CuNG with P-gp. However, CuNG did not compete for the substrate binding as photoaffinity labeling of P-gp with a substrate analog [125I] iodoarylazidoprazosin ([125I] IAAP) showed approximately twofold increase in [125I] IAAP binding in presence of CuNG. In vitro study showed that CuNG significantly stimulated P-gp-specific ATPase activity in isolated membrane preparations from NIH MDR1-G185 cells. This result further confirmed the CuNG–P-gp direct interaction. This study also demonstrated that CuNG has a drug interaction site different from verapamil-, vinblastine- and progesterone-binding sites on P-gp. Taken together, this is the first report of molecular interaction of any Schiff’s base metal chelate CuNG with human P-gp. This information may be useful to design more efficacious nontoxic metal-based drugs as MDR-reversing agents. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular and Cellular Biochemistry Springer Journals

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References (38)

Publisher
Springer Journals
Copyright
Copyright © 2012 by Springer Science+Business Media, LLC.
Subject
Life Sciences; Medical Biochemistry; Oncology; Biochemistry, general; Cardiology
ISSN
0300-8177
eISSN
1573-4919
DOI
10.1007/s11010-012-1232-z
pmid
22258826
Publisher site
See Article on Publisher Site

Abstract

One of the major reasons for multidrug resistance (MDR) in cancer is the overexpression of P-glycoprotein (P-gp, ABCB1), a drug efflux pump. A novel copper complex, namely, copper (II) N-(2-hydroxyacetophenone) glycinate (CuNG) previously synthesized and characterized by the authors had been tested in this study. In a cell-based assay system with human MDR1 cDNA overexpressed mouse fibroblast NIH MDR1-G185 cell line, we demonstrated that this metal complex can directly interact with this transporter. As CuNG increased cellular accumulation of doxorubicin in P-gp-expressing cells, we presumed that of CuNG may be potential to reverse P-gp-mediated drug resistance probably by lowering the P-gp expression at the protein as well as mRNA level. Interestingly, our studies on UIC2 (a conformation sensitive monoclonal antibody) binding assay indicated the direct interaction of CuNG with P-gp. However, CuNG did not compete for the substrate binding as photoaffinity labeling of P-gp with a substrate analog [125I] iodoarylazidoprazosin ([125I] IAAP) showed approximately twofold increase in [125I] IAAP binding in presence of CuNG. In vitro study showed that CuNG significantly stimulated P-gp-specific ATPase activity in isolated membrane preparations from NIH MDR1-G185 cells. This result further confirmed the CuNG–P-gp direct interaction. This study also demonstrated that CuNG has a drug interaction site different from verapamil-, vinblastine- and progesterone-binding sites on P-gp. Taken together, this is the first report of molecular interaction of any Schiff’s base metal chelate CuNG with human P-gp. This information may be useful to design more efficacious nontoxic metal-based drugs as MDR-reversing agents.

Journal

Molecular and Cellular BiochemistrySpringer Journals

Published: Jan 19, 2012

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