Effects of oral iron chelator deferasirox on human malignant lymphoma cells

Jong Gwon Choi; Jung-Lim Kim; Joohee Park; Soonwook Lee; Seh Jong Park; Jun Suk Kim; Chul Won Choi

doi:10.5045/kjh.2012.47.3.194

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Original Article

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Korean J Hematol 2012; 47(3):

Published online September 25, 2012

https://doi.org/10.5045/kjh.2012.47.3.194

Effects of oral iron chelator deferasirox on human malignant lymphoma cells

Jong Gwon Choi¹, Jung-Lim Kim², Joohee Park¹, Soonwook Lee¹, Seh Jong Park¹, Jun Suk Kim¹, and Chul Won Choi^1*

Author Info. +

¹Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea.

²Graduate School of Medicine, Korea University College of Medicine, Seoul, Korea.

Correspondence to : Correspondence to Chul Won Choi, M.D., Ph.D. Department of Internal Medicine, Korea University Guro Hospital, 97, Guro-dong-gil, Guro-gu, Seoul 152-703, Korea. Tel: +82-2-2626-3058, Fax: +82-2-862-4453, bonnie@korea.ac.kr

Received: March 22, 2012; Revised: June 4, 2012; Accepted: August 3, 2012

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Background

Iron is essential for cell proliferation and viability. It has been reported that iron depletion by a chelator inhibits proliferation of some cancer cells. Deferasirox is a new oral iron chelator, and a few reports have described its effects on lymphoma cells. The goal of this study was to determine the anticancer effects of deferasirox in malignant lymphoma cell lines.

Methods

Three human malignant lymphoma cell lines (NCI H28:N78, Ramos, and Jiyoye) were treated with deferasirox at final concentrations of 20, 50, or 100 µM. Cell proliferation was evaluated by an MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry. Western blot analysis was performed to determine the relative activity of various apoptotic pathways. The role of caspase in deferasirox-induced apoptosis was investigated using a luminescent assay.

Results

The MTT assay showed that deferasirox had dose-dependent cytotoxic effects on all 3 cell lines. Cell cycle analysis showed that the sub-G1 portion increased in all 3 cell lines as the concentration of deferasirox increased. Early apoptosis was also confirmed in the treated cells by Annexin V and PI staining. Western blotting showed an increase in the cleavage of PARP, caspase 3/7, and caspase 9 in deferasirox-treated groups.

Conclusion

We demonstrated that deferasirox, a new oral iron-chelating agent, induced early apoptosis in human malignant lymphoma cells, and this apoptotic effect is dependent on the caspase-3/caspase-9 pathway.

Keywords Deferasirox, Malignant lymphoma, Apoptosis

Article

Original Article

Korean J Hematol 2012; 47(3): 194-201

Published online September 25, 2012 https://doi.org/10.5045/kjh.2012.47.3.194

Effects of oral iron chelator deferasirox on human malignant lymphoma cells

Jong Gwon Choi¹, Jung-Lim Kim², Joohee Park¹, Soonwook Lee¹, Seh Jong Park¹, Jun Suk Kim¹, and Chul Won Choi^1*

¹Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea.

²Graduate School of Medicine, Korea University College of Medicine, Seoul, Korea.

Correspondence to: Correspondence to Chul Won Choi, M.D., Ph.D. Department of Internal Medicine, Korea University Guro Hospital, 97, Guro-dong-gil, Guro-gu, Seoul 152-703, Korea. Tel: +82-2-2626-3058, Fax: +82-2-862-4453, bonnie@korea.ac.kr

Received: March 22, 2012; Revised: June 4, 2012; Accepted: August 3, 2012

Abstract

Background

Methods

Results

Conclusion

Keywords: Deferasirox, Malignant lymphoma, Apoptosis

Abstract

Fig 1.

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Figure 1.

MTT assay results show that deferasirox inhibited the proliferation of malignant lymphoma cell lines (A) NCI H28:N78 cells, (B) Jiyoye cells, and (C) Ramos cells. The results are presented as mean (SD) percentage of viability from triplicate cultures with repeated experiments (^a)P<0.05, ^b)P<0.01).

Blood Research 2012; 47: 194-201https://doi.org/10.5045/kjh.2012.47.3.194

Fig 2.

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Figure 2.

Flow cytometry analysis results show that deferasirox treatment increased the percentage of cells in sub-G1 phase in a dose-dependent manner. (A) NCI H28:N78 cells, (B) Jiyoye cells, and (C) Ramos cells. The results are presented as mean (SD) percentage of cells in sub-G1 from triplicate experiments (^a)P<0.05, ^b)P<0.01).

Blood Research 2012; 47: 194-201https://doi.org/10.5045/kjh.2012.47.3.194

Fig 3.

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Figure 3.

Deferasirox induces early apoptosis. Treatment with deferasirox caused dose-dependent apoptosis in 3 malignant lymphoma cell lines (A) NCI H28:N78 cells, (B) Jiyoye cells, and (C) Ramos cells. The experiments were repeated 3 times.

Blood Research 2012; 47: 194-201https://doi.org/10.5045/kjh.2012.47.3.194

Fig 4.

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Figure 4.

Colorimetric assay results show that deferasirox treatment increased caspase-3/7 and caspase-9 activities. Caspase-3/7 and caspase-9 activities were measured after cells were treated with deferasirox for 24 h (A) NCI H28:N78 cells, (B) Jiyoye cells, and (C) Ramos cells (^a)P<0.05, ^b)P<0.01).

Blood Research 2012; 47: 194-201https://doi.org/10.5045/kjh.2012.47.3.194

Fig 5.

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Figure 5.

Western blot analysis of apoptosis-related modulators. Expression of Bax and P53 was upregulated, whereas the expression of Bcl-2 was downregulated after malignant lymphoma cell lines were treated with deferasirox.

Blood Research 2012; 47: 194-201https://doi.org/10.5045/kjh.2012.47.3.194