Andrographolide reverts multidrug resistance in KBChR 8-5 cells through AKT signaling pathway.

Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. P-glycoprotein (P-gp) one of the ATP-binding cassette (ABC) transporters plays an important role in MDR. In this study, we examined the sensitizing property of andrographolide (Andro) to reverse MDR in the drug-resistant KBChR 8-5 cells. Andro exhibited increased cytotoxicity in a concentration-dependent manner in the P-gp overexpressing KBChR 8-5 cells. Furthermore, Andro showed synergistic interactions with PTX and DOX in this drug-resistant cells. Andro co-administration enhanced PTX- and DOX-induced cytotoxicity and reduced cell proliferation in the MDR cancer cells. Moreover, reactive oxygen species (ROS) were elevated with a decrease in the mitochondrial membrane potential (MMP) during Andro and chemotherapeutic drugs combination treatment in the drug-resistant cells. Furthermore, Andro and PTX-induced cell cycle arrest was observed in the drug-resistant cell. We also noticed that the expression of ABCB1 and AKT were downregulated during Andro (4 µM) treatment. Furthermore, Andro treatment enhanced the expression of caspase 3 and caspase 9 in the combinational groups that support the enhanced apoptotic cell death in drug-resistant cancer cells. Therefore, the results reveal that Andro plays a role in the reversal of P-gp-mediated MDR in KBChR 8-5 cells which might be due to regulating ABCB1/AKT signaling pathway.

Reversal of P-glycoprotein-mediated multidrug resistance by natural N-alkylated indole alkaloid derivatives in KB-ChR-8-5 drug-resistant cancer cells.

Multidrug resistance (MDR) remains a significant challenge in cancer chemotherapy due to the overexpression of ATP-binding cassette drug-efflux transporters, namely P-glycoprotein (P-gp)/ATP-binding cassette subfamily B member 1. In this study, derivatives of N-alkylated monoterpene indole alkaloids such as N-(para-bromobenzyl) (NBBT), N-(para-methylbenzyl) (NMBT), and N-(para-methoxyphenethyl) (NMPT) moieties were investigated for the reversal of P-gp-mediated MDR in drug-resistant KB colchicine-resistant 8-5 (KB-ChR-8-5) cells. Among the three indole alkaloid derivatives, the NBBT exhibited the highest P-gp inhibitory activity in a dose-dependent manner. Further, it significantly decreased P-gp overexpression by inactivating the nuclear translocation of the nuclear factor kappa B p-50 subunit. In the cell survival assay, doxorubicin showed 6.3-fold resistance (FR) in KB-ChR-8-5 cells compared with its parental KB-3-1 cells. However, NBBT significantly reduced doxorubicin FR to 1.7, 1.3, and 0.4 and showed strong synergism with doxorubicin for all the concentrations studied in the drug-resistant cells. Furthermore, NBBT and doxorubicin combination decreased the cellular migration and showed increased apoptotic incidence by downregulating Bcl-2, then activating BAX, caspase 3, and p53. The present findings suggest that NBBT could be a lead candidate for the reversal of P-gp- mediated multidrug resistance in cancer cells.