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High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter

Csilla Ozvegy-Laczka1, Tamás Hegedus, György Várady

  • 1National Medical Center, Institute of Hematology and Immunology, Membrane Research Group of the Hungarian Academy of Sciences, Budapest, Hungary.

Molecular Pharmacology
|May 25, 2004
PubMed

Insights

Certain tyrosine kinase inhibitors (TKIs) interact with the ABCG2 transporter, affecting cancer drug efficacy and resistance. This interaction influences cancer treatment outcomes and tumor resistance mechanisms.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • Tyrosine kinase inhibitors (TKIs) target malignant cell growth and metastasis.
  • Intracellular targets of TKIs necessitate understanding membrane transporter roles in drug effectiveness.
  • Hydrophobic TKIs may interact with multidrug transporters, altering cellular drug distribution.

Purpose of the Study:

  • To investigate the direct interaction between clinical-phase TKIs and the ABCG2 multidrug transporter.
  • To determine the affinity and functional consequences of TKI interaction with ABCG2.
  • To assess the impact of TKIs on ABCG2-mediated drug transport and resistance.

Main Methods:

  • In vitro assays to assess TKI interaction with ABCG2.
  • Measurement of ABCG2-ATPase activity modulation by TKIs.
  • Evaluation of ABCG2-dependent active drug extrusion inhibition.
  • Analysis of drug resistance patterns in cells expressing ABCG2.

Main Results:

  • Several TKIs, including imatinib mesylate (STI-571), gefitinib (ZD1839), and EKI-785, demonstrated high-affinity interaction with ABCG2 at submicromolar concentrations.
  • Other multidrug transporters like P-glycoprotein (ABCB1) and ABCC1 showed lower reactivity to these TKIs.
  • TKIs selectively modulated ABCG2-ATPase activity and inhibited ABCG2-dependent drug extrusion.
  • TKIs significantly affected drug resistance patterns in cells expressing ABCG2.

Conclusions:

  • Multidrug resistance protein modulation by TKIs is a significant factor in cancer patient treatment.
  • TKIs may be substrates for efflux by transporters like ABCG2.
  • Tumor cell resistance to TKIs could be mediated by transporter-dependent extrusion.

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