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Title of Journal: Mol Cell Biochem

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Abbravation: Molecular and Cellular Biochemistry

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Springer US

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DOI

10.1016/j.bbabio.2008.05.025

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ISSN

1573-4919

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The molecular interaction of a copper chelate with

Authors: Ruma Dey Ghosh Paramita Chakraborty Kaushik Banerjee Arghya Adhikary Avijit Sarkar Mitali Chatterjee Tanya Das Soumitra Kumar Choudhuri
Publish Date: 2012/01/19
Volume: 364, Issue: 1-2, Pages: 309-320
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Abstract

One of the major reasons for multidrug resistance MDR in cancer is the overexpression of Pglycoprotein Pgp ABCB1 a drug efflux pump A novel copper complex namely copper II N2hydroxyacetophenone glycinate CuNG previously synthesized and characterized by the authors had been tested in this study In a cellbased assay system with human MDR1 cDNA overexpressed mouse fibroblast NIH MDR1G185 cell line we demonstrated that this metal complex can directly interact with this transporter As CuNG increased cellular accumulation of doxorubicin in Pgpexpressing cells we presumed that of CuNG may be potential to reverse Pgpmediated drug resistance probably by lowering the Pgp 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 Pgp However CuNG did not compete for the substrate binding as photoaffinity labeling of Pgp 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 Pgpspecific ATPase activity in isolated membrane preparations from NIH MDR1G185 cells This result further confirmed the CuNG–Pgp direct interaction This study also demonstrated that CuNG has a drug interaction site different from verapamil vinblastine and progesteronebinding sites on Pgp Taken together this is the first report of molecular interaction of any Schiff’s base metal chelate CuNG with human Pgp This information may be useful to design more efficacious nontoxic metalbased drugs as MDRreversing agentsThis work was supported by Financial Grants SR/WOSA/LS89/2007 dated 13092007 from DST New Delhi India We also thank Dr Michael M Gottesman of the National Cancer Institute NIH Bethesda MD USA for the gift of the NIH 3T3 and NIH MDR1G185G185 cell lines We are grateful to Dr Saibal Dey and Dr Debabrata Ghosh of the Uniformed Services University School of Medicine Bethesda MD USA for their assistance in photoaffinitylabeling experiments with IAAP

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