Nilotinib potentiates anticancer drug sensitivity in murine ABCB1-, ABCG2-, and ABCC10-multidrug resistance xenograft models

Cancer Lett. 2013 Jan 28;328(2):307-17. doi: 10.1016/j.canlet.2012.10.001. Epub 2012 Oct 9.

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / chemistry
  • ATP-Binding Cassette Transporters / genetics*
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Drug Synergism
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Molecular Docking Simulation
  • Multidrug Resistance-Associated Proteins / chemistry
  • Multidrug Resistance-Associated Proteins / genetics*
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics*
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Protein Conformation
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays

Substances

  • 4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
  • ABCB1 protein, human
  • ABCC10 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Pyrimidines