Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells
Abstract
:1. Introduction
2. Results
2.1. MK-8776 Restored the Sensitivity of Chemotherapeutics in P-gp-Overexpressing Cancer Cells
2.2. MK-8776 Increased P-gp Substrate [3H]-Paclitaxel Accumulation and Suppressed its Efflux in KB-C2 Cells
2.3. MK-8776 Did Not Alter the Expression of P-gp in KB-C2 Cells
2.4. MK-8776 Did Not Alter P-gp Subcellular Localization
2.5. MK-8776 Stimulated ATPase Activity
2.6. Induced-Fit Docking (IFD) Simulation Interactions between P-gp and MK-8776
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Cell Lines and Cell Culture
4.3. Cytotoxicity experiments
4.4. Western Blot Analysis
4.5. Immunofluorescence Analysis
4.6. ATPase Assay
4.7. [3H]-Paclitaxel Accumulation and Efflux Assay
4.8. Molecular Modeling of Human ABCB1 Homology Model
4.9. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Compounds | IC50 ± SD a (μM) (RF b) | |||
---|---|---|---|---|
KB-3-1 | KB-C2 | HEK293/pcDNA3.1 | HEK293/ABCB1 | |
Doxorubicin | 0.017 ± 0.011 (1.00) | 1.664 ± 0.064 (97.88) | 0.061 ± 0.020 (1.00) | 0.631 ± 0.150 (10.34) |
+ MK-8776 (0.3 μM) | 0.015 ± 0.003 (0.88) | 0.470 ± 0.041 (27.64) * | 0.067 ± 0.017 (1.10) | 0.181 ± 0.014 (2.97) * |
+ MK-8776 (1 μM) | 0.014 ± 0.004 (0.82) | 0.013 ± 0.004 (0.76) * | 0.058 ± 0.027 (0.95) | 0.056 ± 0.033 (0.92) * |
+ Verapmil (3 μM) | 0.014 ± 0.006 (0.82) | 0.016 ± 0.005 (0.94) * | 0.061 ± 0.008 (1.00) | 0.084 ± 0.009 (1.38) * |
Paclitaxel | 0.004 ± 0.002 (1.00) | 2.783 ± 0.053 (695.75) | 0.073 ± 0.027 (1.00) | 3.757 ± 0.312 (51.46) |
+ MK-8776 (0.3 μM) | 0.004 ± 0.001 (1.00) | 0.144 ± 0.013 (36.00) * | 0.122 ± 0.050 (1.67) | 0.255 ± 0.084 (3.49) * |
+ MK-8776 (1 μM) | 0.003 ± 0.001 (0.75) | 0.092 ± 0.004 (23.00) * | 0.100 ± 0.020 (1.37) | 0.047 ± 0.004 (0.64) * |
+ Verapamil (3 μM) | 0.003 ± 0.001 (0.75) | 0.017 ± 0.002 (4.25) * | 0.068 ± 0.003 (0.95) | 0.094 ± 0.003 (1.9) * |
Colchicine | 0.012 ± 0.004 (1.00) | 7.732 ± 0.240 (644.33) | 0.066 ± 0.001 (1.00) | 1.538 ± 0.090 (23.30) |
+ MK-8776 (0.3 μM) | 0.009 ± 0.005 (0.75) | 0.292 ± 0.203 (24.33) * | 0.058 ± 0.007 (0.88) | 0.126 ± 0.106 (1.91) * |
+ MK-8776 (1 μM) | 0.009 ± 0.003 (0.75) | 0.009 ± 0.030 (0.75) * | 0.048 ± 0.009 (0.73) | 0.047 ± 0.021 (0.71) * |
+ Verapamil (3 μM) | 0.008 ± 0.003 (0.66) | 0.006 ± 0.015 (0.5) * | 0.056 ± 0.006 (0.85) | 0.050 ± 0.008 (0.76) * |
Cisplatin | 2.508 ± 0.432 (1.00) | 3.027 ± 0.343 (1.21) | 2.660 ± 0.430 (1.00) | 3.336 ± 0.900 (1.25) |
+ MK-8776 (0.3 μM) | 2.440 ± 0.264 (0.97) | 2.770 ± 0.167 (1.10) | 2.378 ± 0.136 (0.89) | 2.727 ± 0.592 (1.03) |
+ MK-8776 (1 μM) | 2.431 ± 0.179 (0.97) | 2.652 ± 0.087 (1.05) | 2.474 ± 0.286 (0.93) | 2.611 ± 0.353 (0.98) |
+ Verapamil (3 μM) | 2.309 ± 0.641 (0.92) | 2.098 ± 0.230 (0.84) | 2.388 ± 0.452 (0.90) | 3.115 ± 0.433 (1.17) |
Compounds | IC50 ± SD a (μM) (RF b) | |
---|---|---|
SW620 | SW620/Ad300 | |
Doxorubicin | 0.031 ± 0.014 (1.00) | 9.950 ± 2.023 (320.97) |
+ MK-8776 (0.3 μM) | 0.028 ± 0.016 (0.90) | 1.362 ± 0.122 (43.94) * |
+ MK-8776 (1 μM) | 0.035 ± 0.012 (1.13) | 0.426 ± 0.184 (13.74) * |
+ Verapmil (3 μM) | 0.038 ± 0.021 (1.23) | 0.096 ± 0.023 (3.10) * |
Paclitaxel | 0.091 ± 0.015 (1.00) | 21.19 ± 6.25 (232.86) |
+ MK-8776 (0.3 μM) | 0.076 ± 0.038 (0.84) | 1.784 ± 0.125 (19.60) * |
+ MK-8776 (1 μM) | 0.074 ± 0.003 (0.81) | 0.597 ± 0.566 (6.56) * |
+ Verapamil (3 μM) | 0.113 ± 0.006 (1.24) | 0.639 ± 0.023 (7.03) * |
Cisplatin | 1.481 ± 0.676 (1.00) | 1.514 ± 0.398 (1.02) |
+ MK-8776 (0.3 μM) | 1.329 ± 0.156 (0.90) | 1.423 ± 0.438 (0.94) |
+ MK-8776 (1 μM) | 1.228 ± 0.181(0.83) | 1.266 ± 0.295 (0.84) |
+ Verapamil (3 μM) | 1.164 ± 0.107 (0.79) | 1.851 ± 0.364 (1.25) |
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Share and Cite
Cui, Q.; Cai, C.-Y.; Wang, J.-Q.; Zhang, S.; Gupta, P.; Ji, N.; Yang, Y.; Dong, X.; Yang, D.-H.; Chen, Z.-S. Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells. Int. J. Mol. Sci. 2019, 20, 4095. https://doi.org/10.3390/ijms20174095
Cui Q, Cai C-Y, Wang J-Q, Zhang S, Gupta P, Ji N, Yang Y, Dong X, Yang D-H, Chen Z-S. Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells. International Journal of Molecular Sciences. 2019; 20(17):4095. https://doi.org/10.3390/ijms20174095
Chicago/Turabian StyleCui, Qingbin, Chao-Yun Cai, Jing-Quan Wang, Shuang Zhang, Pranav Gupta, Ning Ji, Yuqi Yang, Xingduo Dong, Dong-Hua Yang, and Zhe-Sheng Chen. 2019. "Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells" International Journal of Molecular Sciences 20, no. 17: 4095. https://doi.org/10.3390/ijms20174095
APA StyleCui, Q., Cai, C. -Y., Wang, J. -Q., Zhang, S., Gupta, P., Ji, N., Yang, Y., Dong, X., Yang, D. -H., & Chen, Z. -S. (2019). Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells. International Journal of Molecular Sciences, 20(17), 4095. https://doi.org/10.3390/ijms20174095