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

Abstract

AbstractMultidrug 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.