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Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells.
Int J Mol Sci 2019; 20(17)IJ

Abstract

P-glycoprotein (P-gp), which is encoded by the ATP-binding cassette (ABC) transporter subfamily B member 1 (ABCB1) gene, is one of the most pivotal ABC transporters that transport its substrates across the cell membrane. Its overexpression is one of the confirmed causes of multidrug resistance (MDR), which results in the failure of cancer treatment. Here, we report that checkpoint kinase (Chk) 1 inhibitor MK-8776, a drug candidate in clinical trial, can restore the sensitivity of chemotherapeutics that are substrates of P-gp in KB-C2, SW620/Ad300 cells and human embryonic kidney (HEK)293/ABCB1 cells that overexpress P-gp. MK-8776 remarkably enhanced the cellular [3H]-paclitaxel accumulation and suppressed the efflux function of P-gp without reducing its expression and affecting its cellular localization in cancer cells. Furthermore, MK-8776 (0-40 μM) stimulated the activity of ATPase in P-gp, which was 4.1-fold greater than the control. In addition, MK-8776 formed a cation-π bond and π-π interaction with key residues of the substrate-binding site in P-gp, as indicated by computer-aided molecular docking study. Our study indicated that MK-8776 may significantly enhance the sensitivity of chemotherapeutics that are substrates of P-gp, providing important information for its application in the reversal of MDR.

Authors+Show Affiliations

School of Public Health, Guangzhou Medical University, Guangzhou 511436, China. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.School of Public Health, Guangzhou Medical University, Guangzhou 511436, China.Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. chenz@stjohns.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31443367

Citation

Cui, Qingbin, et al. "Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells." International Journal of Molecular Sciences, vol. 20, no. 17, 2019.
Cui Q, Cai CY, Wang JQ, et al. Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells. Int J Mol Sci. 2019;20(17).
Cui, Q., Cai, C. Y., Wang, J. Q., Zhang, S., Gupta, P., Ji, N., ... 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), doi:10.3390/ijms20174095.
Cui Q, et al. Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells. Int J Mol Sci. 2019 Aug 22;20(17) PubMed PMID: 31443367.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells. AU - Cui,Qingbin, AU - Cai,Chao-Yun, AU - Wang,Jing-Quan, AU - Zhang,Shuang, AU - Gupta,Pranav, AU - Ji,Ning, AU - Yang,Yuqi, AU - Dong,Xingduo, AU - Yang,Dong-Hua, AU - Chen,Zhe-Sheng, Y1 - 2019/08/22/ PY - 2019/08/05/received PY - 2019/08/19/revised PY - 2019/08/21/accepted PY - 2019/8/25/entrez PY - 2019/8/25/pubmed PY - 2019/8/25/medline KW - MK-8776 KW - P-gp KW - multidrug resistance KW - restore KW - sensitivity JF - International journal of molecular sciences JO - Int J Mol Sci VL - 20 IS - 17 N2 - P-glycoprotein (P-gp), which is encoded by the ATP-binding cassette (ABC) transporter subfamily B member 1 (ABCB1) gene, is one of the most pivotal ABC transporters that transport its substrates across the cell membrane. Its overexpression is one of the confirmed causes of multidrug resistance (MDR), which results in the failure of cancer treatment. Here, we report that checkpoint kinase (Chk) 1 inhibitor MK-8776, a drug candidate in clinical trial, can restore the sensitivity of chemotherapeutics that are substrates of P-gp in KB-C2, SW620/Ad300 cells and human embryonic kidney (HEK)293/ABCB1 cells that overexpress P-gp. MK-8776 remarkably enhanced the cellular [3H]-paclitaxel accumulation and suppressed the efflux function of P-gp without reducing its expression and affecting its cellular localization in cancer cells. Furthermore, MK-8776 (0-40 μM) stimulated the activity of ATPase in P-gp, which was 4.1-fold greater than the control. In addition, MK-8776 formed a cation-π bond and π-π interaction with key residues of the substrate-binding site in P-gp, as indicated by computer-aided molecular docking study. Our study indicated that MK-8776 may significantly enhance the sensitivity of chemotherapeutics that are substrates of P-gp, providing important information for its application in the reversal of MDR. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/31443367/Chk1_Inhibitor_MK-8776_Restores_the_Sensitivity_of_Chemotherapeutics_in_P-glycoprotein_Overexpressing_Cancer_Cells L2 - http://www.mdpi.com/resolver?pii=ijms20174095 DB - PRIME DP - Unbound Medicine ER -