Abstract
BackgroundBosutinib is a recently approved ABL inhibitor. In spite of the well-documented effectiveness of BCR-ABL inhibitors in treating chronic myeloid leukemia, development of resistance is a continuous clinical challenge. Transporters that facilitate drug uptake and efflux have been proposed as one potential source of resistance to tyrosine kinase inhibitor treatment. Our aim was to determine which carriers are responsible for bosutinib transport.MethodsK562S cells overexpressing the drug transporters ABCB1, ABCG2, and SLC22A1 were generated, characterized and used in proliferation assay and intracellular uptake and retention assay (IUR). In vivo experiments were performed in nude mice injected with K562S, K562DOX cells (overexpressing ABCB1), and K562DOX silenced for ABCB1 (K562DOX/sh P-GP).ResultsThe IUR assay using C-14 bosutinib showed that only ABCB1 was responsible for active bosutinib transport. K562DOX cells showed the lowest intracellular level of bosutinib, while K562DOX cells treated with the ABCB1 inhibitor verapamil showed intracellular bosutinib levels comparable with parental K562S. Proliferation assays demonstrated that K562DOX are resistant to bosutinib treatment while verapamil is able to restore the sensitivity to the drug. Nude mice injected with K562DOX and treated with bosutinib showed very limited response and quickly relapsed after stopping treatment while K562S as well as K562DOX/sh P-GP remained tumor-free.ConclusionsOur data suggest that the analysis of ABCB1 expression levels might help determine treatment options for patients exhibiting resistance to bosutinib.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0179-4) contains supplementary material, which is available to authorized users.
Highlights
Bosutinib is a recently approved ABL inhibitor
Given that bosutinib is a valuable option for the treatment of chronic myeloid leukemia (CML) patients [4, 17], we examined whether SLC22A1, ABCB1, and ABCG2 are involved in its uptake and efflux with both in vitro assays and an in vivo model
Cell line characterization To investigate the involvement of ABCB1, ABCG2, and SLC22A1 in the active transport of bosutinib, we first characterized expression levels of functionally active drug transporters ABCB1, SLC22A1, and ABCG2 by means of RT-qPCR as well as immunoblotting analysis in the engineered cell lines described in the Materials and methods section
Summary
In spite of the well-documented effectiveness of BCR-ABL inhibitors in treating chronic myeloid leukemia, development of resistance is a continuous clinical challenge. Transporters that facilitate drug uptake and efflux have been proposed as one potential source of resistance to tyrosine kinase inhibitor treatment. Since the discovery of imatinib, the treatment of chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) that selectively target BCR-ABL, the oncoprotein responsible for the disease. [1] Second-generation TKIs such as nilotinib and dasatinib have been recently approved as a first line treatment for CML [2, 3]. Bosutinib is a second-generation dual SRC/ABL TKI, approximately 10–30 times more potent than imatinib, and it was recently approved by FDA as a second line option for CML treatment [4]. Changes in the expression of the drug transporters (downmodulation of SLC22A1 or overexpression of ABCB1 and ABCG2) or single-nucleotide polymorphisms in these genes can cause imatinib resistance [9, 10]
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