Pgp efflux pump decreases the cytostatic effect of CENP-E inhibitor GSK923295.
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.
Charles 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. Electronic address: tchernuk@yahoo.com.
Sergey O
SO
Tcherniuk
Charles E. Schmidt College of Medicine, Department of Biomedical Science, Florida Atlantic University, 777 Glades Road, BC-71, Boca Raton, FL 33431, USA.
Andrew V
AV
Oleinikov
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors*; D054697:Cytostatic Agents / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D012509:Sarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002868:Chromosomal Proteins, Non-Histone; D054697:Cytostatic Agents; C571460:GSK923295; C068688:centromere protein E; D014700:Verapamil; D012521:Sarcosine
Cancer; Chemotherapy; Isobolographic analysis; Kinesin; Multidrug resistance