Abstract
A panel of clinically used tyrosine kinase inhibitors were compared and nilotinib was found to most potently sensitize specific anticancer agents by blocking the functions of ABCB1/P-glycoprotein, ABCG2/BCRP and ABCC10/MRP7 transporters involved in multi-drug resistance. Nilotinib appreciably enhanced the antitumor response of (1) paclitaxel in the ABCB1- and novel ABCC10-xenograft models, and (2) doxorubicin in a novel ABCG2-xenograft model. With no apparent toxicity observed in the above models, nilotinib attenuated tumor growth synergistically and increased paclitaxel concentrations in ABCB1-overexpressing tumors. The beneficial actions of nilotinib warrant consideration as viable combinations in the clinic with agents that suffer from MDR-mediated insensitivity.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / chemistry
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ATP-Binding Cassette Transporters / genetics*
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Drug Resistance, Neoplasm / genetics*
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Drug Synergism
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HEK293 Cells
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Humans
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Male
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Mice
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Mice, Nude
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Molecular Docking Simulation
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Multidrug Resistance-Associated Proteins / chemistry
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Multidrug Resistance-Associated Proteins / genetics*
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Neoplasm Proteins / chemistry
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Neoplasm Proteins / genetics*
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Neoplasms / drug therapy
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Neoplasms / genetics
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Neoplasms / pathology
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Protein Conformation
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / pharmacology*
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Pyrimidines / administration & dosage
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Pyrimidines / pharmacology*
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Tumor Burden / drug effects
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Tumor Burden / genetics
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Xenograft Model Antitumor Assays
Substances
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ABCB1 protein, human
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ABCC10 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 B, Member 1
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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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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Pyrimidines
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nilotinib