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Synthetic isoprenoid photoaffinity labeling of P-glycoprotein specific to multidrug-resistant cells

S Akiyama, A Yoshimura, H Kikuchi, T Sumizawa, M Kuwano and Y Tahara

Department of Cancer Chemotherapy, Faculty of Medicine, Kagoshima University, Japan.

The synthetic isoprenoid N-solanesyl-N,N'-bis(3,4-dimethoxy- benzyl)ethylenediamine (SDB) is known to reverse drug resistance in human multidrug-resistant KB cells. SDB inhibits the photolabeling of P- glycoprotein with the vinblastine analog N-(pazido-(3-(125)l)salicyl)- N'-beta-aminoethylvindesine. We synthesized photoactive radioactive SDB and used it to photoaffinity label membrane vesicles from human KB cells and their multidrug-resistant subline KB-C2 cells. A 150 to 170 kDa protein in membrane vesicles from KB-C2 cells was specifically labeled by the photoanalog of SDB. The labeled band was not detectable in parenteral drug-sensitive cells. The photolabeled 150 to 170 kDa protein was immunoprecipitated with a monoclonal antibody (C219) specific to P-glycoprotein. P-glycoprotein labeling was inhibited by anticancer agents, vinblastine, vincristine, actinomycin D, and daunomycin, with half-maximal inhibition at 2.0, 2.3, 18, and 23 microM, respectively. Only 33 and 18% of the labeling was inhibited by 100 microM Adriamycin and colchicine, respectively. The labeling was also inhibited by agents that reverse multidrug resistance, such as verapamil, reserpine, cepharanthine, and SDB. The existence of other molecules that specifically bind to 125l-SDB-photoanalog was suggested in both KB and KB-C2 membrane vesicles. The fact that we could identify the synthetic isoprenoid acceptor in membrane vesicles from multidrug- resistant cells confirms that P-glycoprotein plays a role in the multidrug resistance phenotype and provides an explanation for the fact that SDB circumvents multidrug resistance.

Volume 36, Issue 5, pp. 730-735, 11/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics




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X.-Q. Ren, T. Furukawa, S. Aoki, T. Nakajima, T. Sumizawa, M. Haraguchi, Z.-S. Chen, M. Kobayashi, and S.-i. Akiyama
Glutathione-dependent Binding of a Photoaffinity Analog of Agosterol A to the C-terminal Half of Human Multidrug Resistance Protein
J. Biol. Chem., June 15, 2001; 276(25): 23197 - 23206.
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