Use of deferasirox, an iron chelator, to overcome imatinib resistance of chronic myeloid leukemia cells.
- Author:
Dae Sik KIM
1
;
Yoo Jin NA
;
Myoung Hee KANG
;
Soo Young YOON
;
Chul Won CHOI
Author Information
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords: Deferasirox; Iron chelator; Chronic myeloid leukemia; Imatinib; Resistance
- MeSH: Antineoplastic Agents/*pharmacology; Apoptosis/drug effects; Apoptosis Regulatory Proteins/metabolism; Benzoates/*pharmacology; Cell Proliferation/drug effects; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm/*drug effects; G1 Phase Cell Cycle Checkpoints/drug effects; Humans; Imatinib Mesylate/*pharmacology; Iron Chelating Agents/*pharmacology; K562 Cells; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*drug therapy/metabolism; Protein Kinase Inhibitors/*pharmacology; Signal Transduction/drug effects; Triazoles/*pharmacology
- From:The Korean Journal of Internal Medicine 2016;31(2):357-366
- CountryRepublic of Korea
- Language:English
- 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 BcrAbl, phosphorylated Bcr-Abl, nuclear factor-kappaB (NF-kappaB) 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-kappaB 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.
