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https://hdl.handle.net/2440/78684
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Type: | Journal article |
Title: | Degree of kinase inhibition achieved in vitro by imatinib and nilotinib is decreased by high levels of ABCB1 but not ABCG2 |
Author: | Eadie, L. Saunders, V. Hughes, T. White, D. |
Citation: | Leukemia and Lymphoma, 2013; 54(3):569-578 |
Publisher: | Taylor & Francis Ltd |
Issue Date: | 2013 |
ISSN: | 1042-8194 1029-2403 |
Statement of Responsibility: | Laura N. Eadie, Verity A. Saunders, Timothy P. Hughes & Deborah L. White |
Abstract: | Imatinib and nilotinib interact with ABCB1 and ABCG2. However, whether they are substrates or inhibitors is a source of conjecture. Here, in vitro, Bcr–Abl kinase inhibition was used to elucidate the impact of ABCB1/ABCG2 overexpression on imatinib and nilotinib transport. High levels of ABCB1 protein in K562-Dox cells resulted in a significantly increased 50% inhibitory concentration (IC₅₀) compared with parental K562 cells for imatinib (IC₅₀(IM); 9 µM to 19 µM, p = 0.002) and nilotinib (IC₅₀(NIL); 345 nM to 620 nM, p = 0.013). This difference was abrogated by ABCB1 inhibitors. However, overexpression of ABCG2 did not significantly increase IC₅₀(IM) or IC₅₀(NIL) or significantly decrease IC₅₀ upon ABCG2 inhibition. Inhibition of ABCB1 but not ABCG2 resulted in a substantial increase in intracellular nilotinib when used at 150 nM but no increase when used at 2 µM. Imatinib and nilotinib appear to be transported by ABCB1 but do not interact strongly with ABCG2. Furthermore, ABCB1 efflux of nilotinib may be concentration-dependent with transport occurring at clinically relevant concentrations. |
Keywords: | CML nilotinib imatinib ABC transporters |
Rights: | © 2013 Informa UK, Ltd. |
DOI: | 10.3109/10428194.2012.715345 |
Published version: | http://dx.doi.org/10.3109/10428194.2012.715345 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
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