Korean J Intern Med.  2016 Mar;31(2):357-366. 10.3904/kjim.2015.024.

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

• Kim DS
• Na YJ
• Kang MH
• Yoon SY
• Choi CW

• KMID: 2373811
• DOI: http://doi.org/10.3904/kjim.2015.024

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.

Keyword

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

MeSH Terms

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
Antineoplastic Agents
Apoptosis Regulatory Proteins
Benzoates
Imatinib Mesylate
Iron Chelating Agents
Protein Kinase Inhibitors
Triazoles