Chemosensitizing potential of andrographolide in P-glycoprotein overexpressing multidrug-resistant cancer cell lines

Abstract

The P-glycoprotein (P-gp) plays a major role in the efflux of chemotherapeutic drugs and significantly limits chemotherapy efficacy. Chemosensitizers augment the therapeutic effects of anticancer agents by overcoming drug resistance mechanisms. In this study, the chemosensitizing property of andrographolide (Andro) in P-gp overexpressing multidrug-resistant (MDR) colchicine-selected KBCh^R 8-5 cells was evaluated. Molecular docking studies showed Andro exhibits higher binding interaction with P-gp than the other two ABC-transporters studied. Further, it inhibits P-gp transport function in a concentration dependant manner in the colchicine-selected KBCh^R 8-5 cells. Moreover, Andro downregulates P-gp overexpression via NF-κB signaling in these MDR cell lines. MTT-based cell-based assay illustrates that Andro treatment augments the PTX effect in the KBCh^R 8-5 cells. Further, the Andro plus PTX combination showed enhanced apoptotic cell death in KBCh^R 8-5 cells compared with PTX alone treatment. Therefore, the results showed that Andro enhances PTX therapeutic effect in the drug-resistant KBCh^R 8-5 cells.

Keywords: Multidrug resistance; P-glycoprotein; andrographolide; chemosensitization; nuclear factor-κB.