Eucalrobusone C suppresses cell proliferation and induces ROS-dependent mitochondrial apoptosis via the p38 MAPK pathway in hepatocellular carcinoma cells
Eucalrobusone C suppresses cell proliferation and induces ROS-dependent mitochondrial apoptosis via the p38 MAPK pathway in hepatocellular carcinoma cells
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Eucalrobusone C 通过 p38 MAPK 通路抑制肝细胞癌细胞增殖并诱导 ROS 依赖性线粒体凋亡
DOI：
10.1016/j.phymed.2016.12.014
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发表时间：
2017-02-15
期刊：
影响因子：
7.9
通讯作者：
Kong, Ling-Yi
中科院分区：
文献类型：
--
作者：
Jian, Kai-Li;Zhang, Chao;Kong, Ling-Yi
背景：桉树提取物对多种癌细胞具有抗肿瘤活性。甲酰间苯三酚类化合物是桉属植物的典型次生代谢物，具有多种重要的药理活性。目的：桉树酮C(Eucalrobusone C，EC)是本实验室首次从桉树叶中分离得到的一种新的生物活性植物化学物质。EC是一种FPM，我们先前的研究表明EC在三种肿瘤模型中显示出比从E.robusta叶中分离的其他化合物更强的细胞毒性。本研究探讨其抗人肝细胞癌的作用及其机制。方法：采用四甲基偶氮唑盐比色法测定细胞存活率。用流式细胞仪检测细胞周期、细胞凋亡率和线粒体跨膜电位。免疫荧光检测采用激光扫描共聚焦显微镜。结果：EC对肝癌细胞具有较强的抗增殖活性，且呈浓度和时间依赖关系。EC通过caspase依赖的线粒体途径显著诱导细胞凋亡，细胞周期停滞于S期。P38 MAPK抑制剂SB203580能有效减少EC诱导的细胞死亡。此外，ROS清除剂N-乙酰半胱氨酸(NAC)显著抑制EC诱导的细胞凋亡，并逆转EC诱导的p38MAPK激活。结论：EC通过ROS的产生和p38MAPK的激活诱导线粒体依赖性的肝癌细胞凋亡，使EC成为一种有前景的抗癌药物。(C)2016年爱思唯尔股份有限公司。
Background: Eucalyptus extracts have anti-cancer activity against various cancer cells. Formylphloroglucinol meroterpenoids (FPMs), which are typical secondary metabolites of the genera Eucalyptus, have many important pharmacological activities.Purpose: Eucalrobusone C (EC), a new bioactive phytochemical, was first isolated from the leaves of Eucalyptus robusta in our laboratory. EC is a FPM, and our previous research revealed that EC showed strongest cytotoxicity in three cancer models than other compounds isolated from the leaves of E. robusta. This study investigated its anti-tumor effects on human hepatocellular carcinoma (HCC) and its underlying mechanisms.Methods: Cell viability was measured by MTT assay. Cell cycle, apoptosis and mitochondrial transmembrane potential were determined by flow cytometry. Immunofluorescence was determined by a laser scanning confocal microscope. Protein levels were analyzed by Western blotting.Results: Our results showed that EC exerted strong anti-proliferative activity against HCC cells in a concentration-and time-dependent manner. EC markedly induced apoptosis through the caspase-dependent mitochondrial pathway, and the cell cycle was arrested at S phase. SB203580, a p38 MAPK inhibitor, effectively decreased cell death caused by EC. Moreover, the ROS scavenger N-acetyl cysteine (NAC) significantly attenuated apoptosis induced by EC and reversed EC-induced p38 MAPK activation.Conclusion: Our findings indicate that EC induces mitochondrial-dependent apoptosis in HCC cells through ROS generation and p38 MAPK activation, making EC a promising candidate for further development as an anticancer agent for HCC cells. (C) 2016 Elsevier GmbH.