Leucoseptoside a reverses multidrug resistance in breast cancer cells by targeting P-glycoprotein (P-gp/ABCB1) transporter.

The overexpression of P-glycoprotein (P-gp) in tumour cells and its mediated drug efflux represent key mechanisms of cancer multidrug resistance (MDR). Natural compounds are attractive candidates for reversing MDR due to their multi-target activity and hypotoxicity. This study evaluated the ability of leucoseptoside A (LeuA) to reverse P-gp-mediated MDR in MCF-7/ADR cells.The MDR reversal activity of LeuA was assessed based on changes in drug sensitivity measured using the MTT assay. P-gp expression was measured by Western blotting. The intracellular accumulation of rhodamine 123 (Rh123) and adriamycin (ADR) was determined using confocal laser scanning microscopy and flow cytometry, and P-gp ATPase activity was assessed using the Pgp-Glo™ system. The binding mode and affinity of LeuA for P-gp were predicted by molecular docking.LeuA markedly enhanced the sensitivity of MCF-7/ADR cells to ADR and paclitaxel (PTX). This mechanism was achieved by inhibiting P-gp efflux rather than altering its protein expression levels. Molecular docking analysis further revealed that LeuA competitively binds to the drug-binding pocket of P-gp with a higher binding affinity than verapamil (VRP).LeuA is a potent reversal agent for P-gp-mediated MDR, promising as a natural inhibitor for cancer therapy.