title: Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells.
abstract: OBJECTIVE
  The treatment of chronic myeloid leukemia (CML) has achieved impressive success since the development of the Bcr-Abl tyrosine kinase inhibitor, imatinib mesylate. Nevertheless, resistance to imatinib has been observed, and a substantial number of patients need alternative treatment strategies.
  
  
  METHODS
  We have evaluated the effects of deferasirox, an orally active iron chelator, and imatinib on K562 and KU812 human CML cell lines. Imatinib-resistant CML cell lines were created by exposing cells to gradually increasing concentrations of imatinib.
  
  
  RESULTS
  Co-treatment of cells with deferasirox and imatinib induced a synergistic dose-dependent inhibition of proliferation of both CML cell lines. Cell cycle analysis showed an accumulation of cells in the subG1 phase. Western blot analysis of apoptotic proteins showed that co-treatment with deferasirox and imatinib induced an increased expression of apoptotic proteins. These tendencies were clearly identified in imatinib-resistant CML cell lines. The results also showed that co-treatment with deferasirox and imatinib reduced the expression of BcrAbl, phosphorylated Bcr-Abl, nuclear factor-κB (NF-κB) and β-catenin.
  
  
  CONCLUSIONS
  We observed synergistic effects of deferasirox and imatinib on both imatinib-resistant and imatinib-sensitive cell lines. These effects were due to induction of apoptosis and cell cycle arrest by down-regulated expression of NF-κB and β-catenin levels. Based on these results, we suggest that a combination treatment of deferasirox and imatinib could be considered as an alternative treatment option for imatinib-resistant CML.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Korea University School of Medicine, Seoul, Korea.
authors.forename: Dae Sik
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Graduate School of Medicine, Korea University School of Medicine, Seoul, Korea.
authors.forename: Yoo Jin
authors.initials: YJ
authors.lastname: Na
authors.affiliation: Graduate School of Medicine, Korea University School of Medicine, Seoul, Korea.
authors.forename: Myoung Hee
authors.initials: MH
authors.lastname: Kang
authors.affiliation: Department of Laboratory Medicine, Korea University School of Medicine, Seoul, Korea.
authors.forename: Soo-Young
authors.initials: SY
authors.lastname: Yoon
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, Korea University School of Medicine, Seoul, Korea.
authors.forename: Chul Won
authors.initials: CW
authors.lastname: Choi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D000077588:Deferasirox; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001565:Benzoates; D007502:Iron Chelating Agents; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D000068877:Imatinib Mesylate; D000077588:Deferasirox
keywords: Chronic myeloid leukemia; Deferasirox; Imatinib; Iron chelator; Resistance