title: Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1).
abstract: OBJECTIVE
  In addition to mutated BCR-ABL1 kinase, the organic cation transporter 1 (OCT1, encoded by SLC22A1) 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.
  
  
  METHODS
  Transport of imatinib was studied using OCT1-expressing Xenopus 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.
  
  
  RESULTS
  Transport and inhibition studies showed that overexpression of functional OCT1 protein in Xenopus 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen; Institute of Pharmacy, Department of Pharmacology, University of Tübingen; Department of Clinical Pharmacology, University Hospital Tübingen, Tübingen; Institute of Experimental and Clinical Pharmacology, Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel; Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany; and Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nies
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Heiko
authors.initials: H
authors.lastname: van der Kuip
authors.forename: Ingolf
authors.initials: I
authors.lastname: Cascorbi
authors.forename: Oliver
authors.initials: O
authors.lastname: Bruhn
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.forename: Christiane
authors.initials: C
authors.lastname: Pott
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.forename: Christopher
authors.initials: C
authors.lastname: Volk
authors.forename: Shuiying
authors.initials: S
authors.lastname: Hu
authors.forename: Sharyn D
authors.initials: SD
authors.lastname: Baker
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001549:Benzamides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001692:Biological Transport; D019008:Drug Resistance, Neoplasm; D005260:Female; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014982:Xenopus laevis
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate