In Vitro and In Vivo Characterizations of Tetrandrine on the Reversal of P-Glycoprotein-mediated Drug Resistance to Paclitaxel

Background: Multidrug resistance (MDR) is one of the major obstacles limiting the efficacy of cancer chemotherapy. Through screening a series of natural products, we have previously identified six naturally occurring bisbenzylisoquinoline alkaloids (BBIs) that possess potent activity to reverse P-glycoprotein (gp)-mediated drug resistance. In this study, we characterized one of these compounds, termed tetrandrine, and evaluated its reversal activity on P-gp-mediated drug resistance to paclitaxel in vitro and in vivo. Materials and Methods: Using the human MDR tumor cell line KBv200 and its drug sensitive parental cell line, the reversal activity of tetrandrine on P-gp-mediated resistance to paclitaxel and docetaxel were determined by MTT and other in vitro drug evaluation assays. Further, through establishment of xenograft models bearing the intrinsically resistant KBv200 tumor, we also examined the effect of tetrandrine on potentiating the antitumor activity of paclitaxel in vivo. Results: In vitro studies showed that co-administration of tetrandrine at 2.5 μM, which has little cytotoxicity alone, reversed the sensitivity of KBv200 cells to paclitaxel and docetaxel around 10-fold. In vivo experiments also demonstrated that tetrandrine significantly potentiated the antitumor activity of paclitaxel in xenograft models bearing the intrinsically resistant KBv200 tumors. In addition, accumulation and efflux studies with [ 3 H]-paclitaxel indicated that tetrandrine increases the intracellular accumulation of [ 3 H]-paclitaxel in MDR cells through inhibition of P-gp-mediated drug efflux. Conclusion: The present in vitro and in vivo studies demonstrated that tetrandrine possesses potent and specific activity in reversing P-gp-mediated drug resistance. This naturally occurring compound may be used as a chemosensitizer in the treatment of P-gp-mediated MDR cancers.