Identification of H7 as a novel peroxiredoxin I inhibitor to induce differentiation of leukemia cells.
Identification of H7 as a novel peroxiredoxin I inhibitor to induce differentiation of leukemia cells.
复制标题
鉴定 H7 作为一种新型过氧化还原蛋白 I 抑制剂来诱导白血病细胞分化。
DOI：
10.18632/oncotarget.6763
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发表时间：
2016-01-26
期刊：
影响因子：
--
通讯作者：
Wu YL
中科院分区：
文献类型：
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作者：
Wei W;Ma C;Cao Y;Yang L;Huang Z;Qin D;Chen Y;Liu C;Xia L;Wang T;Lei H;Yu Y;Huang M;Tong Y;Xu H;Gao F;Zhang J;Wu YL
寻找新的靶点来增强白血病细胞分化是一个迫切的要求。我们最近提出抑制抗氧化酶过氧化物还蛋白I （Prdx I）可能诱导白血病细胞分化。然而，这一概念仍有待证实。在这项工作中，我们通过虚拟筛选、体外活性实验和表面等离子体共振实验确定了H7是一种新的Prdx I抑制剂。细胞热移实验表明，H7在细胞中直接与Prdx I结合，而不与Prdx II-V结合。H7处理还增加了白血病细胞的活性氧（ROS）水平和细胞分化，表现为细胞表面分化标志物CD11b/CD14的上调和细胞形态学成熟。H7在除APL NB4细胞外的部分非急性早幼粒细胞白血病（APL）和原代白血病细胞中也有诱导分化的作用。此外，活性氧清除剂n -乙酰半胱氨酸显著逆转h7诱导的细胞分化。我们也证明了h7诱导的细胞分化与ROS-Erk1/2-C/EBPβ轴的激活有关。最后，我们在APL小鼠模型中展示了H7处理诱导的细胞分化。这些数据证实了Prdx I是诱导白血病细胞分化的新靶点，H7是优化Prdx I抑制的新先导化合物。
Identifying novel targets to enhance leukemia-cell differentiation is an urgent requirment. We have recently proposed that inhibiting the antioxidant enzyme peroxiredoxin I (Prdx I) may induce leukemia-cell differentiation. However, this concept remains to be confirmed. In this work, we identified H7 as a novel Prdx I inhibitor through virtual screening, in vitro activity assay, and surface plasmon resonance assay. Cellular thermal shift assay showed that H7 directly bound to Prdx I but not to Prdxs II–V in cells. H7 treatment also increased reactive oxygen species (ROS) level and cell differentiation in leukemia cells, as reflected by the upregulation of the cell surface differentiation marker CD11b/CD14 and the morphological maturation of cells. The differentiation-induction effect of H7 was further observed in some non-acute promyelocytic leukemia (APL) and primary leukemia cells apart from APL NB4 cells. Moreover, the ROS scavenger N-acetyl cysteine significantly reversed the H7-induced cell differentiation. We demonstrated as well that H7-induced cell differentiation was associated with the activation of the ROS-Erk1/2-C/EBPβ axis. Finally, we showed H7 treatment induced cell differentiation in an APL mouse model. All of these data confirmed that Prdx I was novel target for inducing leukemia-cell differentiation and that H7 was a novel lead compound for optimizing Prdx I inhibition.