title: Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance.
abstract: Multidrug resistance (MDR) is one of the main obstacles in tumor chemotherapy. A promising approach to solving this problem is to utilize a nontoxic and potent modulator able to reverse MDR, which in combination with anticancer drugs increases the anticancer effect. Experiments were carried out to examine the potential of tetrandrine (Tet) as a MDR-reversing agent. Survival of cells incubated with Tet at 2.5 micromol/l for 72 h was over 90%. Tet at 2.5 micromol/l almost completely reversed resistance to vincristine (VCR) in KBv200 cells. Tet at a concentration as low as 0.625 micromol/l produced a 7.6-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive KB cells in vitro. In the KBv200 cell xenograft model in nude mice, neither Tet nor VCR inhibited tumor growth. However, VCR and Tet combined inhibited tumor growth by 45.7%, 61.2% and 55.7% in three independent experimental settings. In the KB cell xenograft model in nude mice, Tet did not inhibit tumor growth, but VCR and the combination of VCR and Tet inhibited tumor growth by 40.6% and 41.6%, respectively. Mechanism studies showed that Tet inhibited [(3)H]azidopine photoaffinity labeling of P-gp and increased accumulation of VCR in MDR KBv200 cells in a concentration-dependent manner. The results suggest that Tet is a potent MDR-reversing agent in vitro and in vivo. Its mechanism of action is via directly binding to P-gp and increasing intracellular VCR accumulation.
authors.affiliation: Cancer Center, Sun Yat-Sen University, 510060 Guangzhou, China. Fulw@gzsums.edu.cn
authors.forename: Liwu
authors.initials: L
authors.lastname: Fu
authors.forename: Yongju
authors.initials: Y
authors.lastname: Liang
authors.forename: Liwen
authors.initials: L
authors.lastname: Deng
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Liming
authors.initials: L
authors.lastname: Chen
authors.forename: Yanli
authors.initials: Y
authors.lastname: Ye
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Yang
authors.forename: Qichao
authors.initials: Q
authors.lastname: Pan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000470:Alkaloids / Q000378:metabolism / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000627:therapeutic use*; D044182:Benzylisoquinolines / Q000378:metabolism / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000473:pathology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007624:KB Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding; D014750:Vincristine / Q000378:metabolism / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D044182:Benzylisoquinolines; C009438:tetrandrine; D014750:Vincristine