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[Cancer Research 64, 2333-2337, April 1, 2004]
© 2004 American Association for Cancer Research

Advances in Brief

Imatinib Mesylate Is a Potent Inhibitor of the ABCG2 (BCRP) Transporter and Reverses Resistance to Topotecan and SN-38 in Vitro

Peter J. Houghton1, Glen S. Germain1, Franklin C. Harwood1, John D. Schuetz2, Clinton F. Stewart2, Elisabeth Buchdunger3 and Peter Traxler3

Departments of 1 Molecular Pharmacology and 2 Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, and 3 Novartis Pharma AG, Basel, Switzerland

Imatinib mesylate (Gleevec, STI571) is a kinase inhibitor selective for Bcr-Abl, activated c-Kit kinases, and platelet-derived growth factor receptor tyrosine kinase. Imatinib mesylate, similar to many other tyrosine kinase inhibitors (TKIs), such as members of the 4-anilinoquinazoline class, competes for ATP binding. Previously, 4-anilinoquinazoline TKIs have been shown to inhibit the function of the breast cancer resistance-associated drug transporter (ABCG2), reversing resistance to camptothecin derivatives topotecan and SN-38. However, the potential to inhibit ABCG2 for the 2-phenylamino-pyrimidine class of TKIs, exemplified by imatinib mesylate, has not been examined. Here, we show that imatinib mesylate potently reverses ABCG2-mediated resistance to topotecan and SN-38 and significantly increases accumulation of topotecan only in cells expressing functional ABCG2. However, overexpression of ABCG2 does not confer resistance to imatinib mesylate. Furthermore, accumulation and efflux of [14C]imatinib mesylate are unaltered between ABCG2-expressing and non-ABCG2-expressing cells or by ATP depletion. These results suggest that imatinib mesylate inhibits the function of ABCG2 but is not a substrate for this transporter.




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Copyright © 2004 by the American Association for Cancer Research.