title: Contrasting effects of diclofenac and ibuprofen on active imatinib uptake into leukaemic cells.
abstract: BACKGROUND
  The human organic cation transporter-1 (OCT-1) is the primary active protein for imatinib uptake into target BCR-ABL-positive cells. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used by chronic myeloid leukaemia (CML) patients on imatinib to manage musculoskeletal complaints.
  
  
  METHODS
  Here we investigated the impact of NSAIDs on functional activity of the OCT-1 (OCT-1 activity; OA) in CML cells.
  
  
  RESULTS
  Although ten of twelve NSAIDs tested had no significant impact on OA (P>0.05), we observed increased OA (27% increase in K562; 22% increase in KU812 cells, P<0.05) and reduced IC50(imatinib) when treated with diclofenac. Co-incubation with imatinib and diclofenac resulted in a significantly lower viable cell number compared with imatinib alone. In contrast, ibuprofen led to a significant decrease in OA, an increase in IC50(imatinib) and thus reduced the cytotoxicity of imatinib. In primary CML samples, diclofenac significantly increased OA, particularly in patients with low OA (<4 ng per 200 000 cells), and significantly decreased IC50(imatinib). Ibuprofen induced significant decreases in OA in CML samples and healthy donors.
  
  
  CONCLUSIONS
  On the basis of the expected impact of these two drugs on OA, ibuprofen should be avoided in combination with imatinib. Further studies are warranted regarding the potential benefit of diclofenac to improve OA in a clinical setting.
authors.affiliation: Department of Hematology, Centre for Cancer Biology/SA Pathology (RAH site), Adelaide, SA, Austarlia.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: T P
authors.initials: TP
authors.lastname: Hughes
authors.forename: C H
authors.initials: CH
authors.lastname: Kok
authors.forename: V A
authors.initials: VA
authors.lastname: Saunders
authors.forename: A
authors.initials: A
authors.lastname: Frede
authors.forename: K
authors.initials: K
authors.lastname: Groot-Obbink
authors.forename: M
authors.initials: M
authors.lastname: Osborn
authors.forename: A A
authors.initials: AA
authors.lastname: Somogyi
authors.forename: R J
authors.initials: RJ
authors.lastname: D'Andrea
authors.forename: D L
authors.initials: DL
authors.lastname: White
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism*; D001549:Benzamides; D045744:Cell Line, Tumor; D004008:Diclofenac / Q000494:pharmacology*; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D020128:Inhibitory Concentration 50; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000187:drug effects*; D010879:Piperazines / Q000378:metabolism*; D011743:Pyrimidines / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001549:Benzamides; D027702:Organic Cation Transporter 1; D010879:Piperazines; D011743:Pyrimidines; D004008:Diclofenac; D000068877:Imatinib Mesylate; D007052:Ibuprofen