The AKT inhibitor, MK-2206, attenuates ABCG2-mediated drug resistance in lung and colon cancer cells

Introduction: The overexpression of ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, are two the major mediators multidrug resistance (MDR) in cancers. Although multiple ABCG2 inhibitors have been developed some undergone evaluation clinical trials, none clinically approved. compound, MK-2206, an inhibitor protein kinases AKT1/2/3, is undergoing trials for treatment certain types cancers, including those resistant to erlotinib. In this vitro study, we conducted experiments determine if MK-2206 attenuates cancer cells overexpressing or transporter. Methodology: efficacy (0.03–1 μM), combination with transporter sub-strates doxorubicin paclitaxel, substrates mitoxantrone, SN-38 topotecan, were determined cell lines, KB-C2 SW620/Ad300, which overexpress H460/MX20 S1-M1-80, transporter, respectively. expression level localization on membranes using western blot immunofluorescence assays, respectively, following incubation MK-2206. Finally, interaction between human was predicted computer-aided molecular modeling. Results: significantly increased anticancer compounds that but not alone μM) did alter viability S1-M1-80 cells, compared incubated vehicle. However, (0.3 1 as indicated by a significant decrease their IC50 values, basal activity ATPase (EC50 = 0.46 its sub-localization membrane. modeling results suggested binds active pocket hydrogen bond, hydrophobic interactions π-π stacking. Conclusion: These data surmounts topotecan If these can be translated humans, it possible could used surmount MDR