Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells

作者：Kim Dae Sik; Na Yoo Jin; Kang Myoung Hee; Yoon Soo Young; Choi Chul Won^*

来源：Korean Journal of Internal Medicine, 2016, 31(2): 357-366.

DOI：10.3904/kjim.2015.024

• Deferasirox
• Iron chelator
• Chronic myeloid leukemia
• Imatinib
• Resistance

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.

• 出版日期2016-3