title: Tivozanib reverses multidrug resistance mediated by ABCB1 (P-glycoprotein) and ABCG2 (BCRP).
abstract: OBJECTIVE
  This study aimed to investigate the mechanism of reversal of multidrug resistance mediated by ABC transporters with tivozanib (AV-951 and KRN-951). Tivozanib is a potent inhibitor of VEGF-1, -2 and -3 receptors.
  
  
  METHODS
  ABCB1- and ABCG2-overexpressing cell lines were treated with respective substrate antineoplastic agents in the presence or absence of tivozanib.
  
  
  RESULTS
  The results indicate that tivozanib can significantly reverse ABCB1-mediated resistance to paclitaxel, vinblastine and colchicine, as well as ABCG2-mediated resistance to mitoxantrone, SN-38 and doxorubicin. Drug efflux assays showed that tivozanib increased the intracellular accumulation of substrates by inhibiting the ABCB1 and ABCG2 efflux activity. Furthermore, at a higher concentration, tivozanib inhibited the ATPase activity of both ABCB1 and ABCG2 and inhibited the photolabeling of ABCB1 or ABCG2.
  
  
  CONCLUSIONS
  We conclude that tivozanib at noncytotoxic concentrations has the previously unknown activity of reversing multidrug resistance mediated by ABCB1 and ABCG2 transporters.
authors.affiliation: Laboratory of Dermatology, Xiangya Hospital, Changsha, Hunan, China.
authors.forename: Danwen
authors.initials: D
authors.lastname: Yang
authors.forename: Rishil J
authors.initials: RJ
authors.lastname: Kathawala
authors.forename: Eduardo E
authors.initials: EE
authors.lastname: Chufan
authors.forename: Atish
authors.initials: A
authors.lastname: Patel
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Zhe-Sheng
authors.initials: ZS
authors.lastname: Chen
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D020128:Inhibitory Concentration 50; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000633:toxicity; D011804:Quinolines / Q000494:pharmacology* / Q000633:toxicity; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D011804:Quinolines; C553176:tivozanib; D040262:Receptors, Vascular Endothelial Growth Factor; D000251:Adenosine Triphosphatases
keywords: ABC transporter; ABCB1; ABCG2; multidrug resistance; tivozanib; tyrosine kinase inhibitor