Imatinib Mesylate Is a Potent Inhibitor of the ABCG2 (BCRP) Transporter and Reverses Resistance to Topotecan and SN-38 in Vitro
| Autor: | Peter J. Houghton, Peter Traxler, Glen S. Germain, Clinton F. Stewart, Franklin C. Harwood, John D. Schuetz, Elisabeth Buchdunger |
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| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
animal structures Abcg2 Antineoplastic Agents Bone Neoplasms Pharmacology Irinotecan Piperazines Growth factor receptor Cell Line Tumor hemic and lymphatic diseases medicine ATP Binding Cassette Transporter Subfamily G Member 2 Humans Enzyme Inhibitors neoplasms Osteosarcoma biology Chemistry Kinase Topoisomerase Neoplasm Proteins Pyrimidines Imatinib mesylate Oncology Drug Resistance Neoplasm Benzamides embryonic structures Imatinib Mesylate Cancer research biology.protein ATP-Binding Cassette Transporters Camptothecin Topotecan sense organs Tyrosine kinase medicine.drug |
| Zdroj: | Cancer Research. 64:2333-2337 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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