Circumvention of P-glycoprotein-mediated multiple drug resistance by phosphorylation modulators is independent of protein kinases

Charles Smith, J. T. Zilfou

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

Expression 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 4α- and 4β-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 [3H]vinblastine. These effects of 4β-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 [3H]vinblastine, and antagonized photolabeling of P-glycoprotein by [3H]azidopine. Therefore, phosphorylation does not appear to play a significant role in regulating P- glycoprotein activity in MCF-7/ADR cells.

Original languageEnglish (US)
Pages (from-to)28145-28152
Number of pages8
JournalJournal of Biological Chemistry
Volume270
Issue number47
DOIs
StatePublished - Jan 1 1995

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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