Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells
| Autor: | Cornelia Brendel, Susan E. Bates, Gunther Wennemuth, U Boudriot, Ying Wang, Andreas Neubauer, Marius Dohse, Suneet Shukla, Suresh V. Ambudkar, Robert W. Robey, C Scharenberg, Andreas Burchert |
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| Rok vydání: | 2007 |
| Předmět: |
Cancer Research
Abcg2 medicine.drug_class Antineoplastic Agents Biology Piperazines Tyrosine-kinase inhibitor Mice Recurrence Transduction Genetic Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine ATP Binding Cassette Transporter Subfamily G Member 2 Animals Humans Protein Kinase Inhibitors Binding Sites Hematopoietic stem cell Imatinib Hematology Hematopoietic Stem Cells Neoplasm Proteins Haematopoiesis Pyrimidines Imatinib mesylate medicine.anatomical_structure Oncology Nilotinib Drug Resistance Neoplasm Benzamides Imatinib Mesylate Cancer research biology.protein ATP-Binding Cassette Transporters Stem cell K562 Cells medicine.drug |
| Zdroj: | Leukemia. 21:1267-1275 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/sj.leu.2404638 |
| Popis: | The majority of chronic phase chronic myeloid leukemia (CML) patients treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate maintain durable responses to the drug. However, most patients relapse after withdrawal of imatinib and advanced stage patients often develop drug resistance. As CML is considered a hematopoietic stem cell cancer, it has been postulated that inherent protective mechanisms lead to relapse in patients. The ATP binding-cassette transporters ABCB1 (MDR-1; P-glycoprotein) and ABCG2 are highly expressed on primitive hematopoietic stem cells (HSCs) and have been shown to interact with TKIs. Herein we demonstrate a dose-dependent, reversible inhibition of ABCG2-mediated Hoechst 33342 dye efflux in primary human and murine HSC by both imatinib and nilotinib (AMN107), a novel aminopyrimidine inhibitor of BCR-ABL. ABCG2-transduced K562 cells were protected from imatinib and nilotinib-mediated cell death and from downregulation of P-CRKL. Moreover, photoaffinity labeling revealed interaction of both TKIs with ABCG2 at the substrate binding sites as they compete with the binding of [(125)I] IAAP and also stimulate the transporter's ATPase activity. Therefore, our evidence suggests for the role of ABC transporters in resistance to TKI on primitive HSCs and CML stem cells and provides a rationale how TKI resistance can be overcome in vivo. |
| Databáze: | OpenAIRE |
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