白皮杉醇 C 通过 p38 MAPK 通路抑制肝癌细胞增殖并诱导 ROS 依赖性线粒体凋亡。
Eucalrobusone C suppresses cell proliferation and induces ROS-dependent mitochondrial apoptosis via the p38 MAPK pathway in hepatocellular carcinoma cells.
机构信息
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, People's Republic of China.
出版信息
Phytomedicine. 2017 Feb 15;25:71-82. doi: 10.1016/j.phymed.2016.12.014. Epub 2016 Dec 23.
BACKGROUND
Eucalyptus extracts have anti-cancer activity against various cancer cells. Formyl-phloroglucinol 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.
背景
桉树提取物对各种癌细胞具有抗癌活性。甲酰基间苯三酚倍半萜类化合物（FPMs）是桉树属的典型次生代谢产物，具有许多重要的药理活性。
目的
Eucalrobusone C（EC）是一种新型生物活性植物化学物质，首次从我们实验室的桉树叶片中分离得到。EC 是一种 FPM，我们之前的研究表明，EC 在三种癌症模型中的细胞毒性最强，比从桉树叶片中分离得到的其他化合物更强。本研究探讨了其对人肝癌（HCC）的抗肿瘤作用及其潜在机制。
方法
通过 MTT 法测定细胞活力。通过流式细胞术测定细胞周期、凋亡和线粒体膜电位。通过激光共聚焦显微镜测定免疫荧光。通过 Western blot 分析蛋白水平。
结果
我们的结果表明，EC 对 HCC 细胞表现出强烈的浓度和时间依赖性增殖抑制活性。EC 通过 caspase 依赖的线粒体途径显著诱导细胞凋亡，细胞周期被阻滞在 S 期。p38 MAPK 抑制剂 SB203580 可有效降低 EC 引起的细胞死亡。此外，ROS 清除剂 N-乙酰半胱氨酸（NAC）可显著减轻 EC 诱导的细胞凋亡，并逆转 EC 诱导的 p38 MAPK 激活。
结论
我们的研究结果表明，EC 通过 ROS 生成和 p38 MAPK 激活诱导 HCC 细胞线粒体依赖性凋亡，使 EC 成为进一步开发 HCC 细胞抗癌药物的有前途的候选物。
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