Dithiolation indolizine exerts viability suppression effects on A549 cells via triggering intrinsic apoptotic pathways and inducing G2/M phase arrest
Dithiolation indolizine exerts viability suppression effects on A549 cells via triggering intrinsic apoptotic pathways and inducing G2/M phase arrest
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DOI：
10.1016/j.biopha.2020.110961
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发表时间：
2021-01-01
影响因子：
7.5
通讯作者：
Huang，Hongliang
中科院分区：
文献类型：
--
作者：
Li，Guanting;Wu，Xianwei;Huang，Hongliang
中氮茚衍生物已被报道用于治疗许多疾病。然而，对非小细胞肺癌（NSCLC）的研究很少。合成了一系列中氮茚类化合物。MTT法显示化合物8（C8）对A549细胞的增殖有明显的抑制作用，而C8（15、30 μg/mL）对其他细胞株（SH-SY 5 Y、HepG 2和BEAS-2B细胞）的细胞毒性较小; Hoechst染色和JC-1染色显示C8可引起A549细胞核形态改变，线粒体膜电位降低。流式细胞仪检测结果显示，C8使细胞周期阻滞于G2 / M期，细胞内ROS水平升高，细胞凋亡比例增加。采用免疫印迹法检测细胞凋亡和细胞周期相关蛋白的表达水平。这些结果证实了内质网应激（ERS）和PI 3 K/Akt介导的线粒体途径协同触发细胞凋亡。此外，PI 3 K/Akt抑制剂和p53抑制剂的应用进一步证明了上述论点，C8诱导的A549细胞周期阻滞主要受p53调控。C8诱导的ROS含量的积累参与线粒体损伤。化合物处理A549细胞后，其增殖受到抑制，从而诱导细胞凋亡和周期阻滞。C8（二硫代中氮茚）是一个潜在的抗非小细胞肺癌的候选化合物。
Indolizine derivatives have been reported for the treatment of numerous diseases. However, few studies were carried out for non-small cell lung cancer (NSCLC). We synthesized series of indolizine compounds. The results of MTT assay showed compound 8 (C8) markedly inhibited the proliferation of A549 cells, however, C8 (15, 30 μg/mL) had little cytotoxicity in other cell lines (SH-SY5Y, HepG2, and BEAS-2B cells), Hoechst staining and JC-1 staining showed that C8 induced changes in the nucleus morphology, increased the loss in mitochondrial membrane potential in A549 cells. The results of flow cytometry manifested that cell cycle of the cells was arrested in the G2 / M phase by C8, ROS levels and the proportion of apoptosis of cells increased. We performed western blotting analysis to detect the expression levels of apoptosis and cycle-related proteins. These results validated that the apoptosis of cells was triggered by endoplasmic reticulum stress (ERS) and the PI3K/Akt-mediated mitochondrial pathway collaboratively. Besides, the utilization of PI3K/Akt inhibitors and p53 inhibitors further proves the above argument and C8-induced cycle arrest of A549 cells is majorly regulated by p53. C8 induced the accumulation of ROS contents involved in mitochondrial damage. The proliferation of A549 cells was inhibited after treatment with the compound, which induced apoptosis and cycle arrest of cells. It is suggested that C8(dithiolation indolizine) is a potential candidate compound against non-small cell lung cancer.