title: HZ08 reverse P-glycoprotein mediated multidrug resistance in vitro and in vivo.
abstract: BACKGROUND
  Multidrug efflux transporter P-glycoprotein (P-gp) is highly expressed on membrane of tumor cells and is implicated in resistance to tumor chemotherapy. HZ08 is synthesized and studied in order to find a novel P-gp inhibitor.
  
  
  METHODS
  MDCK-MDR1 monolayer transport, calcein-AM P-gp inhibition and P-gp ATPase assays were used to confirm the P-gp inhibition capability of HZ08. Furthermore, KB-WT and KB-VCR cells were used to evaluate the P-gp inhibitory activity of HZ08 both in vitro and in vivo.
  
  
  RESULTS
  Results showed that HZ08 was more potent than verapamil in MDCK-MDR1 monolayer transportation model. Meanwhile, P-gp ATPase assay and calcein-AM P-gp inhibition assay confirmed that HZ08 inhibited P-gp ATPase with a calcein-AM IC50 of 2.44±0.31μM. In addition, significantly greater in vitro multidrug resistance reversing effects were observed when vincristine or paclitaxel was used in combination with 10μM HZ08 compared with 10μM verapamil. Moreover, HZ08 could significantly enhance the sensitivity of vincristine with a similar effect like verapamil in both KB-WT and KB-VCR tumor xenograft models.
  
  
  CONCLUSIONS
  The novel structure HZ08 could be a potent P-gp inhibitor.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Zheyi
authors.initials: Z
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, China.
authors.forename: Zaigang
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yahui
authors.initials: Y
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, China.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007624:KB Cells; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D007546:Isoquinolines; C524509:N-cyano-1-((3,4-dimethoxyphenyl)methyl)-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide; D044005:Tetrahydroisoquinolines; D014700:Verapamil; C083501:Elacridar