Data from Cellular Uptake of Imatinib into Leukemic Cells Is Independent of Human Organic Cation Transporter 1 (OCT1)

Abstract

<div>Abstract<p><b>Purpose:</b> In addition to mutated BCR-ABL1 kinase, the organic cation transporter 1 (OCT1, encoded by <i>SLC22A1</i>) has been considered to contribute to imatinib resistance in patients with chronic myeloid leukemia (CML). As data are conflicting as to whether OCT1 transports imatinib and may serve as a clinical biomarker, we used a combination of different approaches including animal experiments to elucidate comprehensively the impact of OCT1 on cellular imatinib uptake.</p><p><b>Experimental Design:</b> Transport of imatinib was studied using OCT1-expressing <i>Xenopus</i> oocytes, mammalian cell lines (HEK293, MDCK, V79) stably expressing OCT1, human leukemic cells, and Oct1-knockout mice. OCT1 mRNA and protein expression were analyzed in leukemic cells from patients with imatinib-naïve CML as well as in cell lines.</p><p><b>Results:</b> Transport and inhibition studies showed that overexpression of functional OCT1 protein in <i>Xenopus</i> oocytes or mammalian cell lines did not lead to an increased cellular accumulation of imatinib. The CML cell lines (K562, Meg-01, LAMA84) and leukemic cells from patients expressed neither OCT1 mRNA nor protein as demonstrated by immunoblotting and immunofluorescence microscopy, yet they showed a considerable imatinib uptake. Oct1 deficiency in mice had no influence on plasma and hepatic imatinib concentrations.</p><p><b>Conclusions:</b> These data clearly demonstrate that cellular uptake of imatinib is independent of OCT1, and therefore OCT1 is apparently not a valid biomarker for imatinib resistance. <i>Clin Cancer Res; 20(4); 985–94. ©2013 AACR</i>.</p></div>