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Theresa S. Chu, BS; Jocelyn S. Chen, BS; Jay Patrick Lopez, BA; Francisco S. Pardo, MD; Joseph Aguilera, BS; Weg M. Ongkeko, MD, PhD

Arch Otolaryngol Head Neck Surg. 2008;134(9):979-984.

Objective  To investigate whether the mechanism for the reversal of ABCG2 (also known as ABCP, MXR, and BCRP)–mediated drug resistance by imatinib mesylate (Gleevec, STI571; Novartis Pharmaceuticals Corp, East Hanover, New Jersey) is caused by the downregulation of Akt kinase. The adenosine triphosphatase–binding cassette protein ABCG2 has been suggested to be involved in the resistance against various anticancer drugs. Recent studies show that imatinib reverses ABCG2-mediated drug resistance to topotecan hydrochloride and SN-38. In addition, we have previously reported that imatinib downregulates Akt kinase activity, which is elevated in head and neck squamous cell carcinoma.

Design  Flow cytometric analysis was used to determine the levels of drug or dye extrusion from the cells.

Results  We used Akt kinase inhibitors, transfection with short interfering RNA (siRNA) Akt, and the tyrosine kinase inhibitor imatinib to show that these treatments decreased the side population by 50% to 70% in Hoechst 33342 extrusion studies. Doxorubicin hydrochloride extrusion experiments also demonstrated 20% to 26% decrease in doxorubicin efflux on cells treated with imatinib, 1L6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate, and transfection with siRNA Akt. With Western blot and immunofluorescence experiments, our data suggest that ABCG2 translocation is the mechanism by which imatinib and Akt regulate drug resistance. Clonogenic survival assays performed with imatinib-treated cells resulted in a dose-dependent decrease in cell survival compared with the control population.

Conculsion  Our findings demonstrate that imatinib confers greater doxorubicin retention, presumably via inhibition of Akt, which regulates ABCG2 function.

Author Affiliations: Division of Head and Neck Surgery, Department of Surgery (Mss Chu and Chen, Mr Lopez, and Dr Ongkeko), and Division of Radiation Oncology, Department of Radiology (Mr Aguilera), University of California, San Diego, and Department of Biology, San Diego State University (Dr Pardo), San Diego.
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