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Smith CD , Zilfou JT
Circumvention of P-Glycoprotein-Mediated Multiple-Drug Resistance by Phosphorylation Modulators Is Independent of Protein-Kinases
Journal of Biological Chemistry. 1995 Nov 24;270(47) :28145-28152
AbstractExpression of P-glycoprotein by tumor cells confers resistance to multiple natural product drugs because of its ability to export these compounds, This transporter is a substrate for several protein kinases; however, the functional significance of its phosphorylation is not defined, We examined the effects of many activators and inhibitors of protein kinases on the activity of P-glycoprotein in drug-resistant human breast carcinoma cells (MCF-7/ADR), Several phorbol esters sensitized these cells to P-glycoprotein substrate drugs; however, there was no correlation with activation of protein kinase C. The 4 alpha- and 4 beta-isomers of phorbol 12-myristate 13-acetate were equally potent in sensitizing the cells to actinomycin D and daunomycin and in increasing the intracellular accumulation of [H-3]vinblastine. These effects of 4 beta-phorbol myristate acetate required much higher concentrations than were needed to increase P-glycoprotein phosphorylation and were not antagonized by staurosporine, Similar to verapamil, the phorbol esters did not sensitize MCF-7/ADR cells to cisplatin, nor parental MCF-7 cells to any of the anticancer drugs, Mezerein, K-252a, and H-89 sensitized MCF-7/ADR cells, increased intracellular accumulation of [H-3]vinblastine, and antagonized photolabeling of P-glycoprotein by [H-3]azidopine. Therefore, phosphorylation does not appear to play a significant role in regulating P-glycoprotein activity in MCF-7/ADR cells.
NotesTimes Cited: 28 Article TG210 J BIOL CHEM