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  • Letter to the Editor
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Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2

Leukemia volume 22, pages 445–447 (2008)Cite this article

This letter addresses the concerns raised in a series of reports published as letters to the editor in a recent issue of Leukemia (2007) (vol. 21, issue 7) about the role of P-glycoprotein (Pgp) or ABCB1 (ATP Binding Cassette) and ABCG2 in both in vitro and in vivo resistance to imatinib mesylate (Gleevec or STI-571). Rumpold et al.1 demonstrated that silencing the expression of Pgp in imatinib-resistant chronic myeloid leukemia (CML) cell lines re-sensitized the cells to both imatinib and doxorubicin. Similarly, Widmer et al.2 developed an analytical method to determine the imatinib content in cellular extracts and showed that the intracellular concentration of imatinib increased by 4- to 9-fold in K562 cells expressing Pgp. They further concluded that the restoration of the imatinib sensitivity observed in these resistant CML cell lines was due to the marked increase in intracellular levels of imatinib. These reports are consistent with the previously published finding that imatinib is a substrate for Pgp and its active efflux by this transporter results in low intracellular concentrations.3 However, other studies4, 5 showed that overexpression of Pgp in K562 cells does not confer resistance to imatinib, nor did the specific elimination of Pgp in the hematopoietic system improve the responses of imatinib in a CML animal model. Zong et al.5 showed that the leukemia initiating cells were not sensitized to imatinib by loss of Pgp, which indicated that there was a very minimal role for Pgp in resistance to imatinib in an in vivo system. They further proposed that one of the possible reasons for not getting positive indications in Pgp-mediated resistance to imatinib in in vivo conditions was because of the inhibitory effect of imatinib on not only Pgp but also other ABC transporters. These authors further speculated that the inhibitory effect of imatinib on these transporters could be because of the possible competition of imatinib with ATP for the nucleotide-binding domain of the ABC transporters because imatinib shares a structural similarity with ATP and has been shown to bind to the ATP-binding pocket in BCR ABL-kinase.6

Taken together, in this report, we have used the ATP binding and the vanadate trapping assay to show for the first time that imatinib does not interact at the ATP-binding sites of either Pgp or ABCG2 despite their strong affinity for the ATP-binding pocket of the tyrosine kinases and that it behaves like a transport substrate as it stimulates ATP hydrolysis by these transporters. Using IAAP, we also provide direct evidence for the interaction of imatinib at the transport substrate-binding site(s) of both Pgp and ABCG2. This strengthens the argument that this class of the TKIs are the substrates of the ABC-drug transporters. We suggest that this may also result in development of resistance to this class of drugs in chronic-phase CML patients due to the expression of ABC-drug transporters in addition to the mutation(s) in the tyrosine kinases.

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Acknowledgements

We thank Samrawit Tekle and Dr Krishnamachary Nandigama for their assistance with some of the experiments and George Leiman for editorial assistance. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

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  1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), DHHS, Bethesda, MD, USA

    S Shukla, Z E Sauna & S V Ambudkar

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  1. S Shukla
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Correspondence to S V Ambudkar.

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Shukla, S., Sauna, Z. & Ambudkar, S. Evidence for the interaction of imatinib at the transport-substrate site(s) of the multidrug-resistance-linked ABC drug transporters ABCB1 (P-glycoprotein) and ABCG2. Leukemia 22, 445–447 (2008). https://doi.org/10.1038/sj.leu.2404897

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