title: In vitro and in vivo characterizations of tetrandrine on the reversal of P-glycoprotein-mediated drug resistance to paclitaxel.
abstract: 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.
  
  
  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 microM, 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 [3H]-paclitaxel indicated that tetrandrine increases the intracellular accumulation of [3H]-paclitaxel in MDR cells through inhibition of P-gp-mediated drug efflux.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Xueming
authors.initials: X
authors.lastname: Zhu
authors.forename: Meihua
authors.initials: M
authors.lastname: Sui
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000470:Alkaloids / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D044182:Benzylisoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007624:KB Cells; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D044182:Benzylisoquinolines; C009438:tetrandrine; D017239:Paclitaxel