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  • Title: The molecular interaction of a copper chelate with human P-glycoprotein.
    Author: Ghosh RD, Chakraborty P, Banerjee K, Adhikary A, Sarkar A, Chatterjee M, Das T, Choudhuri SK.
    Journal: Mol Cell Biochem; 2012 May; 364(1-2):309-20. PubMed ID: 22258826.
    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 [(125)I] iodoarylazidoprazosin ([(125)I] IAAP) showed approximately twofold increase in [(125)I] 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.
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