Distinct Interaction of Nilotinib and Imatinib with P-Glycoprotein in Intracellular Accumulation and Cytotoxicity in CML Cell Line K562 Cells
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概要
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Nilotinib, a second-generation tyrosine kinase inhibitor (TKI), has been approved for first-line chronic myeloid leukemia (CML) treatment. The improved clinical response of nilotinib over that of the first generation TKI, imatinib, has been thought to be a result of its high potency of inhibition of BCR-ABL kinase. This study aimed to characterize differences between nilotinib and imatinib in the intracellular accumulation and cytotoxic effect on the CML cell line K562. Accumulation of nilotinib in K562 cells was from 4.7- to 9.0-fold higher than that of imatinib. The cytotoxic effect of nilotinib on K562 cells was 14.2-fold higher than that of imatinib. Inhibition experiments in K562 cells, and examination of the cellular uptake using influx transporter-transfected human embryonic kidney (HEK) 293 cells, suggested that the influx transporters OCT1 and OATP1A2, which have been reported to mediate accumulation of imatinib in CML cells, contributed little to the uptake of nilotinib. Nilotinib was found to accumulate in imatinib-resistant K562 (K562/IM) cells overexpressing the efflux transporter P-glycoprotein (P-gp), although cytotoxic assays showed that K562/IM cells displayed 20000-fold greater resistance to nilotinib over the parent K562 cells. In conclusion, the present findings suggest that intracellular accumulation of nilotinib in CML cells contributes to its clinical response and efficacy in CML patients. Although nilotinib has been reported to be effective against imatinib-resistant ABL kinase mutants, the drug could not overcome imatinib resistance acquired by P-gp-overexpression. These results imply that classification of mechanisms of drug resistance is important for suitable strategies to treat imatinib-resistant CML patients.
- 公益社団法人 日本薬学会の論文
著者
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Sato Daisuke
Department of Cardio-angiology, Kitasato University School of Medicine
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Yuki Misato
Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto
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Kawaguchi Tatsuya
Department Of Hematology And Infectious Diseases Kumamoto University Graduate School Of Medical Scie
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Yamakawa Yuji
Department of Clinical Pharmaceutical Sciences, School of Pharmaceutical Sciences, Kumamoto University
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Yuki Misato
Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University
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Uchida Takashi
Department of Clinical Pharmaceutical Sciences, School of Pharmaceutical Sciences, Kumamoto University
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Hayashi Masahiro
Department of Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
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SAITO Hideyuki
Department of Clinical Pharmaceutical Sciences, Faculty of Life Science, Kumamoto University
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Hayashi Masahiro
Department of Pharmacy, Toranomon Hospital
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Hamada Akinobu
Division of Translational Research, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
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