Tivozanib reverses multidrug resistance mediated by ABCB1 (P-glycoprotein) and ABCG2 (BCRP)

Future Oncol. 2014 Aug;10(11):1827-41. doi: 10.2217/fon.13.253. Epub 2013 Dec 3.

Abstract

Aim: 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.

Materials & 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.

Conclusion: We conclude that tivozanib at noncytotoxic concentrations has the previously unknown activity of reversing multidrug resistance mediated by ABCB1 and ABCG2 transporters.

Keywords: ABC transporter; ABCB1; ABCG2; multidrug resistance; tivozanib; tyrosine kinase inhibitor.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / metabolism
  • Adenosine Triphosphatases / metabolism
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / genetics*
  • Enzyme Activation / drug effects
  • Gene Expression
  • Humans
  • Inhibitory Concentration 50
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Phenylurea Compounds / pharmacology*
  • Phenylurea Compounds / toxicity
  • Quinolines / pharmacology*
  • Quinolines / toxicity
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Phenylurea Compounds
  • Quinolines
  • tivozanib
  • Receptors, Vascular Endothelial Growth Factor
  • Adenosine Triphosphatases