Abstract
A multi-center study from the French Myelodysplastic Syndrome (MDS) Group confirmed that iron chelation therapy is an independent prognostic factor that can increase the survival rate of patients who are suffering from transfusion-dependent low-risk MDS. In this study, we aimed to explore this clinical phenomena in vitro, by exploring the synergistic effect of the iron chelator Deferasirox (DFX) and the DNA methyl transferase inhibitor Decitabine (DAC) in the leukemia cell lines SKM-1, THP-1, and K-562. Treatment with both DFX or DAC promoted apoptosis, induced cell cycle arrest, and inhibited proliferation in all three of these cell lines. The combination of DFX and DAC was much greater than the effect of using either drug alone. DFX showed a synergistic effect with DAC on cell apoptosis in all three cell lines and on cell cycle arrest at the G0/G1 phase in K-562 cells. DFX decreased the ROS levels to varying degrees. In contrast, DAC increased ROS levels and an increase in ROS was also noted when the two drugs were used in combination. Treatment of cells with DAC induced re-expression of ABAT, APAF-1, FADD, HJV, and SMPD3, presumably through demethylation. However the combination of DAC and DFX just had strong synergistic effect on the re-expression of HJV.
Highlights
Myelodysplastic syndrome (MDS) is a malignant condition of bone marrow stem cells
A multi-center study from the French Myelodysplastic Syndrome (MDS) Group confirmed that iron chelation therapy is an independent prognostic factor that can increase the survival rate of patients who are suffering from transfusion-dependent low-risk MDS
To evaluate anti-proliferative effects, the three leukemia cell lines, SKM-1, THP-1, and K-562 cells were treated with DAC, DFX, or a combination of DAC and DFX for 24, 48, 72, 96, and 120 h
Summary
Myelodysplastic syndrome (MDS) is a malignant condition of bone marrow stem cells. It is characterized by ineffective hemopoiesis of stem or progenitor cells, which leads to peripheral blood cytopenias and may progress to acute myeloid leukemia in some patients [1]. The most frequent treatment given to patients with MDS is supportive care. This has led a substantial subgroup of MDS patients to eventually develop transfusion dependency, resulting in secondary iron overload in which elevation of serum ferritin (SF), heart failure, and liver dysfunction are often observed [4]. Since the body has no physiological mechanism to excrete excess iron, in order to avoid secondary iron overload, patients receiving long-term blood transfusion should be treated with iron chelation therapy (ICT) according to the MDS Foundation’s guidelines [5]
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