Background Multidrug resistance (MDR) in cancer is one of the main obstacles in treatment with chemotherapy. Drug efflux through P-glycoprotein is the major mechanism involved in MDR. A potential strategy to provide the best possible clinical outcomes is to develop P-glycoprotein (P-gp) inhibitors from natural products. Purpose The present study investigated the effects of the natural sesquiterpene lactone tenulin and its derivative isotenulin on human P-gp; the mechanisms of kinetic interactions were also explored. Methods The human P-gp (ABCB1/Flp-In™-293) stable expression cells were established by using the Flp-In™ system. The effects of tenulin and isotenulin on cell viability were evaluated by SRB assays in established cell lines, sensitive cancer cell line (HeLaS3), and resistant cancer cell line (KB-vin). The transporter inhibition ability was evaluated by calcein-AM uptake assays. The P-gp inhibition kinetics of tenulin and isotenulin were evaluated by rhodamine123 and doxorubicin efflux assays. The ATPase activity was evaluated with the Pgp-Glo™ Assay System. Results Tenulin and isotenulin significantly inhibited the P-gp efflux function by stimulating P-gp ATPase activity. Tenulin and isotenulin interacted with the effluxes of rhodamine 123 and doxorubicin through a competitive and noncompetitive mechanism, respectively. The combinations of tenulin and isotenulin with chemotherapeutic drugs significantly resensitized MDR cancer cells. Conclusion These results suggested that tenulin and isotenulin are potential candidates to be developed for synergistic treatment of MDR cancers.
