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Type: Journal article
Title: Dasatinib cellular uptake and efflux in chronic myeloid leukemia cells: therapeutic implications
Author: Hiwase, D.
Saunders, V.
Hewett, D.
Frede, A.
Zrim, S.
Dang, P.
Eadie, L.
To, L.
Vaz de Melo, J.
Kumar, S.
Hughes, T.
White, D.
Citation: Clinical Cancer Research, 2008; 14(12):3881-3888
Publisher: Amer Assoc Cancer Research
Issue Date: 2008
ISSN: 1078-0432
Statement of
Devendra K. Hiwase, Verity Saunders, Duncan Hewett, Amity Frede, Stephanie Zrim, Phuong Dang, Laura Eadie, L. Bik To, Junia Melo, Sharad Kumar, Timothy P. Hughes and Deborah L. White
Abstract: Purpose: The organic cation transporter OCT-1 mediates active transport of imatinib. We recently showed that low OCT-1 activity is a major contributor to suboptimal response in chronic myeloid leukemia (CML) patients treated with imatinib. The relevance of OCT-1 activity and efflux pumps in determining intracellular uptake and retention (IUR) of dasatinib was assessed. Experimental Design: The effect of OCT inhibitors on [14C]dasatinib and [14C]imatinib IUR was compared using peripheral blood mononuclear cells from newly diagnosed CML patients. The role of efflux transporters was studied using ABCB1- and ABCG2-overexpressing cell lines and relevant inhibitors. Results: Unlike imatinib, there was no significant difference in the dasatinib IUR at 37°C and 4°C (P = 0.8), and OCT-1 inhibitors including prazosin did not reduce dasatinib IUR significantly. In CML mononuclear cells, prazosin inhibitable IUR was significantly higher for imatinib than dasatinib (6.38 versus 1.48 ng/200,000 cells; P = 0.002; n = 11). Patients with high OCT-1 activity based on their imatinib uptake had IC50dasatinib values equivalent to patients with low OCT-1 activity. Dasatinib IUR was significantly lower in ABCB1-overexpressing cell lines compared with parental cell lines (P < 0.05). PSC833 (ABCB1 inhibitor) significantly increased the dasatinib IUR (P < 0.05) and reduced IC50dasatinib (from 100 to 8 nmol/L) in K562-DOX cell line. The ABCG2 inhibitor Ko143 significantly increased dasatinib IUR in ABCG2-overexpressing cell lines and reduced IC50dasatinib. Conclusion: Unlike imatinib, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of both efflux proteins, ABCB1 and ABCG2.
Keywords: HL-60 Cells
K562 Cells
Tumor Cells, Cultured
ATP-Binding Cassette Transporters
Organic Cation Transporter 1
Neoplasm Proteins
Fusion Proteins, bcr-abl
Antineoplastic Agents
Drug Evaluation, Preclinical
Inhibitory Concentration 50
Biological Transport
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Imatinib Mesylate
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP Binding Cassette Transporter, Subfamily B
ATP Binding Cassette Transporter, Subfamily B, Member 1
Description: Copyright © 2008 American Association for Cancer Research
DOI: 10.1158/1078-0432.CCR-07-5095
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