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
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / genetics*
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ATP-Binding Cassette Transporters / metabolism
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Adenosine Triphosphatases / metabolism
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm / genetics*
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Enzyme Activation / drug effects
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Gene Expression
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Humans
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Inhibitory Concentration 50
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Phenylurea Compounds / pharmacology*
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Phenylurea Compounds / toxicity
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Quinolines / pharmacology*
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Quinolines / toxicity
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
Substances
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ABCB1 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antineoplastic Agents
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Neoplasm Proteins
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Phenylurea Compounds
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Quinolines
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tivozanib
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Receptors, Vascular Endothelial Growth Factor
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Adenosine Triphosphatases