Ethyl acetate extract of Caesalpinia sappan L. inhibited acute myeloid leukemia via ROS-mediated apoptosis and differentiation.,Phytomedicine

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Ethyl acetate extract of Caesalpinia sappan L. inhibited acute myeloid leukemia via ROS-mediated apoptosis and differentiation.
Phytomedicine ( IF 6.7 ) Pub Date : 2019-12-04 , DOI: 10.1016/j.phymed.2019.153142
Hao-Yue Ma ₁ , Cheng-Qiang Wang ₁ , Hui He ₁ , Zan-Yang Yu ₁ , Yao Tong ₁ , Gen Liu ₁ , Yu-Qi Yang ₁ , Li Li ₁ , Lei Pang ₁ , Hong-Yi Qi ₁

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BACKGROUND The dried heartwood of Caesalpinia sappan L. is traditionally prescribed in the formula of traditional Chinese medicine (TCM) for the treatment of acute myeloid leukemia (AML), while nothing is yet known of the active fractions and the underlying mechanisms. PURPOSE This study aims to investigate the effect of the ethyl acetate extract of the dried heartwood of Caesalpinia sappan L. (C-A-E) on induction of apoptosis and promotion of differentiation in vitro and anti-AML activity in vivo. STUDY DESIGN/METHODS The aqueous extract was sequentially separated with solvents of increasing polarity and the active fraction was determined through the inhibition potency. The inhibition of the active fraction on cell viability, proliferation and colony formation was performed in different AML cells. Induction of apoptosis and the promotion of differentiation were further determined. Then, the level of the reactive oxygen species (ROS) and its potential role were assessed. Finally, anti-AML activity was evaluated in NOD/SCID mice. RESULTS C-A-E exhibited the highest inhibition on the cell viability of HL-60 cells. Meanwhile, C-A-E significantly suppressed the proliferation and the colony formation ability of HL-60 and Kasumi-1 cells. Moreover, C-A-E significantly induced the apoptosis, which was partially reversed by Z-VAD-FMK. C-A-E also reduced the level of mitochondrial membrane potential, promoted the release of cytochrome C, decreased the Bcl-2/Bax ratio, and promoted the cleavage of caspase-9 and -3. In addition, Mdivi-1 (mitochondrial fission blocker) remarkably reduced the apoptosis caused by C-A-E. Meanwhile, C-A-E also induced the expression of Mff and Fis1 and increased the location of Drp1 in mitochondria. Furthermore, C-A-E obviously promoted the differentiation of AML cells characterized by the typic morphological changes, the increased NBT positive cells, as well as the increased CD11b and CD14 levels. Notably, C-A-E significantly enhanced the intracellular ROS level. Moreimportantly, C-A-E-mediated apoptosis and differentiation of HL-60 cells was significantly mitigated by NAC. Additionally, C-A-E also exhibited an obvious anti-AML effect in NOD/SCID mice with the injection of HL-60 cells. CONCLUSIONS C-A-E exhibited an inhibitory effect on AML cells by inducing mitochondrial apoptosis and promoting differentiation, both of which were highly correlated to the activation of ROS.

中文翻译：

es草的乙酸乙酯提取物通过ROS介导的凋亡和分化抑制急性髓细胞性白血病。

背景技术传统上，在传统的中药（TCM）配方中规定了用于治疗急性髓性白血病（AML）的凯撒es（Casealpinia sappan L.）的干燥心材，而活性成分及其潜在机理尚不清楚。目的本研究旨在研究Ca木（Caesalpinia sappan L.）干心材的乙酸乙酯提取物（CAE）在体外诱导凋亡和促进分化以及体内抗AML活性的作用。研究设计/方法将水提取物依次用极性增加的溶剂分离，并通过抑制力确定活性级分。在不同的AML细胞中进行有效成分对细胞活力，增殖和集落形成的抑制作用。进一步确定了细胞凋亡的诱导和分化的促进。然后，评估了活性氧（ROS）的水平及其潜在作用。最后，在NOD / SCID小鼠中评估了抗AML活性。结果CAE对HL-60细胞的细胞活力具有最高的抑制作用。同时，CAE显着抑制HL-60和Kasumi-1细胞的增殖和集落形成能力。而且，CAE显着诱导了细胞凋亡，其被Z-VAD-FMK部分逆转。CAE还降低了线粒体膜电位水平，促进了细胞色素C的释放，降低了Bcl-2 / Bax比，并促进了caspase-9和-3的裂解。此外，Mdivi-1（线粒体裂变阻滞剂）显着减少了CAE引起的细胞凋亡。同时，CAE还诱导线粒体中Mff和Fis1的表达并增加Drp1的位置。此外，CAE明显促进了AML细胞的分化，其特征是典型的形态变化，NBT阳性细胞增加以及CD11b和CD14水平增加。值得注意的是，CAE显着提高了细胞内ROS水平。更重要的是，NAC显着减轻了CAE介导的HL-60细胞凋亡和分化。另外，通过注射HL-60细胞，CAE在NOD / SCID小鼠中也表现出明显的抗AML作用。结论CAE通过诱导线粒体凋亡和促进分化而对AML细胞具有抑制作用，两者均与ROS的激活高度相关。

更新日期：2019-12-04

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