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

Abstract

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 MDRin 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 nuclearfactor 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.