An Isoquinolin-1(2H)-Imine Derivative Induces Cell Death via Generation of Reactive Oxygen Species and Activation of JNK in Human A549 Cancer Cells.
An Isoquinolin-1(2H)-Imine Derivative Induces Cell Death via Generation of Reactive Oxygen Species and Activation of JNK in Human A549 Cancer Cells.
复制标题
Isoquinolin-1(2H)-Imine 衍生物通过在人 A549 癌细胞中产生活性氧并激活 JNK 来诱导细胞死亡。
DOI：
10.1002/jcb.26093
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发表时间：
2017
影响因子：
4
通讯作者：
Zhang Jihong
中科院分区：
文献类型：
--
作者：
Liu Jing;Liu Tongyang;Mou Hanchuan;Jia Shuting;Huang Chao;Yan Shengjiao;Lin Jun;Luo Ying;Zhang Jihong
化合物11 -苯甲酰- 10 -氯- 7,9 -二氟- 6 -亚胺- 2,3,4,6 -四氢- 1H -嘧啶[1,2 - b]异喹啉- 8 -碳腈（HC6h）是一种新型的多环1,3 -重氮杂环融合异喹啉- 1(2H) -亚胺衍生物，具有良好的体内抗癌活性和低毒性。然而，其潜在的抗癌机制尚未被确定。MTT法检测A549的增殖情况。用H2DCFDA探针检测A549的活性氧（ROS）水平。采用JC‐1染色法测定线粒体膜电位。annexin - V/PI法检测细胞凋亡，吖啶橙染色和GFP - LC3荧光法检测细胞自噬。Western blot检测细胞自噬蛋白和凋亡蛋白的表达。化合物HC6h增加A549细胞中囊泡、吖啶橙染色细胞和LC3 - II的积累。巴菲霉素A1抑制化合物HC6h诱导的自噬可增加细胞凋亡。化合物HC6h增强了A549细胞中caspase - 3、caspase - 9的活化和PARP的裂解。化合物HC6h导致细胞内ROS的快速生成。此外，化合物HC6h诱导JNK磷酸化，并由ROS水平升高引起。此外，JNK的下调可减弱HC6h对细胞自噬和凋亡的影响。HC6h处理后ROS的诱导导致JNK的激活，JNK介导人A549癌细胞的自噬和凋亡。j .细胞。中国生物医学工程学报，2017,31(2):444 - 444。©2017 Wiley期刊公司
Compound 11‐benzoyl‐10‐chloro‐7,9‐difluoro‐6‐imino‐2,3,4,6‐tetrahydro‐1H‐pyrimido[1,2‐b]isoquinoline‐8‐carbonitrile (HC6h) is a novel polyhalo 1,3‐diazaheterocycle fused isoquinolin‐1(2H)‐imines derivative, which displays good anticancer activity and low toxicity in vivo. However, the underlying anticancer mechanisms have not previously been identified. The proliferation of A549 was assessed by MTT assay. The reactive oxygen species (ROS) level was assessed in A549 with a H2DCFDA probe. Mitochondrial membrane potential was measured using the JC‐1 staining. Apoptosis were measured by annexin‐V/PI assay and autophagy by acridine orange staining and GFP‐LC3 fluorescence assay. The expression of autophagic and apoptotic proteins was determined by Western blot. The compound HC6h increased accumulation of vesicles, acridine orange‐stained cells and LC3‐II in A549 cells. Inhibition of compound HC6h‐induced autophagy by bafilomycin A1 increased apoptosis. Compound HC6h enhanced activation of caspase‐3, caspase‐9 and PARP cleavage in A549 cells. Compound HC6h leads to the rapid generation of intracellular ROS. Moreover, compound HC6h induced phosphorylation of JNK and was conferred by the increased ROS levels. Furthermore, down‐regulation of JNK attenuated autophagic and apoptotic effect in response to HC6h. The induction of ROS upon HC6h treatment leads to the activation of JNK that mediates autophagy and apoptosis in human A549 cancer cells. J. Cell. Biochem. 118: 4394–4403, 2017. © 2017 Wiley Periodicals, Inc.