The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
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Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells

  • Kim, Dae Sik (Division of Hematology and Oncology, Department of Internal Medicine, Korea University School of Medicine) ;
  • Na, Yoo Jin (Graduate School of Medicine, Korea University School of Medicine) ;
  • Kang, Myoung Hee (Graduate School of Medicine, Korea University School of Medicine) ;
  • Yoon, Soo-Young (Department of Laboratory Medicine, Korea University School of Medicine) ;
  • Choi, Chul Won (Division of Hematology and Oncology, Department of Internal Medicine, Korea University School of Medicine)
  • Received : 2015.02.02
  • Accepted : 2015.03.30
  • Published : 2016.03.01
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Abstract

Background/Aims: 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 Bcr-Abl, phosphorylated Bcr-Abl, nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$) and ${\beta}-catenin$. 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 $NF-{\kappa}B$ and ${\beta}-catenin$ 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.

Keywords

Acknowledgement

Supported by : Korea University

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