Li Nianyi, Chen Qinfen, Gu Jingwen, Li Shuang, Zhao Guangjie, Wang Wei, Wang Zhicheng, Wang Xiaoqin
Department of Haematology, Huashan Hospital, Fudan University, Shanghai, China.
Oncotarget. 2017 May 30;8(22):36517-36530. doi: 10.18632/oncotarget.16583.
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.
法国骨髓增生异常综合征（MDS）研究小组的一项多中心研究证实，铁螯合疗法是一个独立的预后因素，可提高输血依赖型低危MDS患者的生存率。在本研究中，我们旨在通过探索铁螯合剂地拉罗司（DFX）和DNA甲基转移酶抑制剂地西他滨（DAC）在白血病细胞系SKM-1、THP-1和K-562中的协同作用，在体外探究这一临床现象。单独使用DFX或DAC进行治疗均能促进这三种细胞系的细胞凋亡、诱导细胞周期停滞并抑制细胞增殖。DFX与DAC联合使用的效果远大于单独使用任一药物的效果。DFX在所有三种细胞系中均与DAC对细胞凋亡具有协同作用，并且在K-562细胞中与DAC对细胞周期停滞于G0/G1期具有协同作用。DFX能不同程度地降低活性氧（ROS）水平。相比之下，DAC会提高ROS水平，并且当两种药物联合使用时也会出现ROS水平升高的情况。用DAC处理细胞可诱导ABAT、APAF-1、FADD、HJV和SMPD3的重新表达，推测这是通过去甲基化实现的。然而，DAC与DFX的联合使用仅对HJV的重新表达具有强烈的协同作用。
