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

• We have analyzed the influence of the Pgp efflux pump on the cytostatic effect of GSK923295.
• We used Pgp null MESSA cells and Pgp overexpressing MESSA Dx5 cells.
• Pgp overexpression reduces the antiproliferative effect of GSK923295 in MESSA Dx5 cells.
• Combinations of GSK923295 with verapamil produce an additive effect in MESSA cells.
• Combinations of GSK923295 with verapamil produce a synergetic effect in MESSA Dx5 cells.

Human kinesin CENP-E is an attractive target for cancer chemotherapy. The allosteric CENP-E inhibitor GSK923295 was proposed as a promising anticancer compound with potent cytostatic effect. In our work, we have analyzed the influence of the Pgp efflux pump on the cytostatic effect of GSK923295. We have demonstrated that multidrug resistant MESSA Dx5 cells overexpressing Pgp are 70–80 times more resistant to GSK923295 than their parental counterpart MESSA cells. Addition of 20 µM verapamil restored the drug sensibility of MESSA Dx5 cells. Combinations of GSK923295 with verapamil showed nearly additive effects in MESSA and synergistic effects in MESSA Dx5 cells. Our results demonstrate that tumors possessing Pgp could be more resistant to GSK923295, and that overexpression of Pgp can decrease the therapeutic effect of this drug. Development of structural analogs of GSK923295 which would not be a substrate of the Pgp efflux pump or addition of Pgp pump inhibitors can significantly improve the cytostatic effect of this drug.