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Imatinib-mediated inactivation of Akt regulates ABCG2 function in head and neck squamous cell carcinoma

Theresa S Chu1, Jocelyn S Chen, Jay Patrick Lopez

  • 1Division of Head and Neck Surgery, Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.

Archives of Otolaryngology--Head & Neck Surgery
|September 17, 2008
PubMed
Abstract

Insights

Imatinib reverses ABCG2-mediated drug resistance by downregulating Akt kinase, leading to increased doxorubicin retention in cancer cells. This mechanism enhances the efficacy of chemotherapy by improving drug accumulation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • ABCG2 (ATP-binding cassette sub-family G member 2) is implicated in multidrug resistance.
  • Imatinib mesylate has shown potential in reversing ABCG2-mediated drug resistance.
  • Akt kinase activity is elevated in certain cancers and may be linked to drug resistance.

Purpose of the Study:

  • To elucidate the mechanism by which imatinib mesylate reverses ABCG2-mediated drug resistance.
  • To investigate the role of Akt kinase downregulation in this reversal process.
  • To determine if imatinib's effect on Akt kinase is responsible for overcoming drug resistance.

Main Methods:

  • Flow cytometry was used to assess drug/dye extrusion.
  • Inhibitors of Akt kinase and imatinib were employed.
  • Short interfering RNA (siRNA) targeting Akt was utilized for gene silencing.
  • Western blot and immunofluorescence confirmed protein translocation.
  • Clonogenic survival assays evaluated cell viability.

Main Results:

  • Imatinib, Akt inhibitors, and Akt siRNA reduced Hoechst 33342 extrusion by 50-70%.
  • Doxorubicin hydrochloride efflux decreased by 20-26% with imatinib and Akt siRNA treatment.
  • Data suggest ABCG2 translocation is regulated by imatinib and Akt, mediating drug resistance.
  • Clonogenic assays showed a dose-dependent decrease in cell survival with imatinib.

Conclusions:

  • Imatinib enhances doxorubicin retention in cancer cells.
  • This retention is likely due to the inhibition of Akt kinase.
  • Akt kinase regulates the function of ABCG2, impacting drug resistance.

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