Mutually co-operative interactions between modulators of p-glycoprotein

You Ming Shao, Suhail Ayesh, Wilfred D. Stein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

We measured the effects of combinations of verapamil, vinblastine, mefloquine, and tamoxifen, all being modulators of the multidrug resistance pump, P-glycoprotein, on the accumulation of labelled daunomycin into multidrug-resistant -388 leukemia cells at 37°C. We found that, contrary to our initial expectations (based on Ayesh, Shao and Stein (1996) Biochim. Biophys. Acta 1316, 8), vinblastine, mefloquine, and tamoxifen all appeared to interact with one another synergistically, i.e. by the kinetics of a non-competitive interaction. A simple kinetic analysis showed that pairs of co-operating modulators can give apparent non-competitive behaviour, but refined kinetic analysis enables the two types of interaction to be distinguished. The modulators vinblastine, mefloquine, and tamoxifen thus appear to co-operate with one another in pairs to bring about reversal of β-glycoprotein. This may have important implications for the design of new modulators of P-glycoprotein.

Original languageEnglish
Pages (from-to)30-38
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1360
Issue number1
DOIs
StatePublished - 27 Feb 1997

Keywords

  • Behavior, non-competitive
  • Cooperativity
  • Kinetics
  • Modulator
  • Multidrug resistance
  • P-glycoprotein

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