Pgp efflux pump decreases the cytostatic effect of CENP-E inhibitor GSK923295

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Functional Assessment of Kinesin-7 CENP-E in Spermatocytes Using In Vivo Inhibition, Immunofluorescence and Flow Cytometry
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Functional Assessment of Kinesin-7 CENP-E in Spermatocytes Using In Vivo Inhibition, Immunofluorescence and Flow Cytometry

Published on: December 28, 2021

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Sergey O Tcherniuk1, Andrew V Oleinikov2

  • 1Charles E. Schmidt College of Medicine, Department of Biomedical Science, Florida Atlantic University, 777 Glades Road, BC-71, Boca Raton, FL 33431, USA; Department of Biological Sciences, Youth Academy of Sciences of Ukraine, 12-B Kachtanovaya str., 02225 Kiev, Ukraine.

Cancer Letters
|March 1, 2015
PubMed

Insights

The P-glycoprotein (Pgp) efflux pump significantly reduces the effectiveness of the anticancer drug GSK923295. Inhibiting Pgp restores drug sensitivity, improving its potential for cancer chemotherapy.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Human kinesin CENP-E is a validated target for cancer chemotherapy.
  • GSK923295, an allosteric CENP-E inhibitor, exhibits potent cytostatic effects.
  • The P-glycoprotein (Pgp) efflux pump is implicated in multidrug resistance.

Purpose of the Study:

  • To investigate the impact of the Pgp efflux pump on the cytostatic efficacy of GSK923295.
  • To evaluate the potential of Pgp inhibition to overcome resistance to GSK923295.

Main Methods:

  • Comparison of GSK923295 sensitivity in Pgp-overexpressing cells (MESSA Dx5) versus parental cells (MESSA).
  • Assessment of drug response upon co-administration with verapamil, a Pgp inhibitor.
  • Analysis of drug interaction effects (additive vs. synergistic).

Main Results:

  • MESSA Dx5 cells showed 70-80 fold increased resistance to GSK923295 compared to MESSA cells.
  • Verapamil (20 µM) restored GSK923295 sensitivity in MESSA Dx5 cells.
  • Combinations exhibited additive effects in MESSA cells and synergistic effects in MESSA Dx5 cells.

Conclusions:

  • Tumors expressing Pgp may exhibit resistance to GSK923295, diminishing its therapeutic effect.
  • Strategies involving Pgp-non-substrate analogs or Pgp inhibitors could enhance GSK923295's cytostatic activity.
Keywords:
CancerChemotherapyIsobolographic analysisKinesinMultidrug resistance

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