Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells
P-glycoprotein (P-gp), encoded by the ATP-binding cassette (ABC) transporter subfamily B member 1 (ABCB1) gene, is a crucial ABC transporter responsible for moving substrates across the cell membrane. Its overexpression is a well-established cause of multidrug resistance (MDR), leading to the failure of cancer treatments. In this study, we demonstrate that the checkpoint kinase (Chk) 1 inhibitor MK-8776, a drug currently undergoing clinical trials, can restore the sensitivity of chemotherapeutic agents that are P-gp substrates in KB-C2, SW620/Ad300, and human embryonic kidney (HEK)293/ABCB1 cells with P-gp overexpression. MK-8776 significantly increased cellular accumulation of [3H]-paclitaxel and inhibited P-gp’s efflux activity without altering its expression or cellular localization in cancer cells. Moreover, MK-8776 (0-40 μM) enhanced P-gp ATPase activity by 4.1-fold compared to the control. Molecular docking studies revealed that MK-8776 forms both cation-π and π-π interactions with key residues of P-gp’s substrate-binding site. These findings suggest that MK-8776 can significantly improve the sensitivity of chemotherapeutics that are P-gp substrates, offering valuable insights into its potential for reversing MDR.