南方医科大学学报

南方医科大学学报 ›› 2021, Vol. 41 ›› Issue (9): 1319-1328.doi: 10.12122/j.issn.1673-4254.2021.09.05

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川芎通过多成分、多靶点、多信号通路和多生物学功能发挥抗肺癌脑转移作用

徐廉松，黄富豪，张语涵，牛雯雯，庞金龙，李姗姗，李 娴   

  1. 蚌埠医学院，安徽 蚌埠 233030；中药饮片制造新技术安徽省重点实验室，安徽 亳州 236800；安徽协和成药业饮片有限公司博士后工作站，安徽 亳州 236800
  • 出版日期:2021-09-20 发布日期:2021-09-30

Chuanxiong Rhizoma inhibits brain metastasis of lung cancer through multiple active ingredients acting on multiple targets, pathways and biological functions

XU Liansong, HUANG Fuhao, ZHANG Yuhan, NIU Wenwen, PANG Jinlong, LI Shanshan, LI Xian   

  1. Bengbu Medical College, Bengbu 233030, China; Key Laboratory of Anhui Province for New Technology of Chinese Medicine Decoction Pieces Manufacturing, Bozhou 236800, China; Postdoctoral Workstation of Anhui Xiehecheng Pharmaceutical Decoction Pieces Co., Ltd., Bozhou 236800, China
  • Online:2021-09-20 Published:2021-09-30

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摘要： 目的 利用网络药理学方法和分子对接技术研究川芎治疗肺癌脑转移的潜在分子机制。方法 通过中药系统药理学分析平台TCMSP数据库获取川芎的化学成分和作用靶点；通过GeneCards数据库筛选肺癌脑转移的相关靶点；借助Clusterpro-filerR包进行GO和KEGG富集分析；利用Cytoscape及STRING数据库构建川芎“活性成分-靶点-疾病”网络、蛋白相互作用网络，根据拓扑学参数筛选川芎治疗肺癌脑转移的核心成分及作用靶点，并将两者进行分子对接；最后，通过川芎处理人肺癌细胞PC9，运用Western blot法检测相关蛋白表达对核心靶点进行初步验证。结果 本研究共筛选出（Z）-藁本内酯、丁苯酞、油酸、杨梅酮等48个有效成分；INS、BDNF、FOS、VEGFA、PTGS2、ESR1、MAPK14、PTGS1等49个靶点蛋白；核受体活性、配体激活、转录因子活性等57个生物学功能；Prolactin signaling pathway、Breastcancer、Etrogen signaling pathway等40条信号通路。分子对接结果显示，杨梅酮、丁苯酞、4-羟基-3丁基苯酞、（Z）藁本内酯、洋川芎内酯-E等成分与BDNF、FOS、PTGS2、MAPK14等7个核心靶点有较强亲和能力。Western blot结果显示，0.1 mol/L和1 mol/L川芎处理肺癌细胞PC9后PI3K的磷酸化水平分别为（86.51±13.09）%、（71.58±5.56）%，AKT的磷酸化水平分别为（87.49±13.09）%、（71.47±13.02）%，VEGF的水平分别为（84.39± 8.95）%、（80.65±10.07）%，且差异均具有统计学意义（P<0.01）。结论 川芎通过多成分、多靶点、多信号通路和多生物学功能发挥抗肺癌脑转移的作用。

关键词: 川芎；网络药理学；分子对接；肺癌脑转移

Abstract: Objective To explore the molecular mechanism mediating the inhibitory effect of Chuanxiong Rhizoma against brain metastasis of lung cancer using network pharmacology methods and molecular docking. Methods The chemical components of Chuanxiong Rhizoma and their targets were obtained through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The relevant targets for brain metastasis of lung cancer were screened using the GeneCards database. Clusterpro-filerR package was used to perform GO and KEGG enrichment analysis. Cytoscape and STRING database were used to construct the "active ingredient- target-disease" network and protein-protein interaction (PPI) network of Chuanxiong Rhizoma. The core components of Chuanxiong Rhizoma and their targets in the treatment of lung cancer brain metastasis were screened based on the topological parameters, and the results were verified using molecular docking and in Chuanxiong extract- treated human lung cancer PC9 cells by detecting the core target with Western blotting. Results Forty-eight active ingredients of Chuanxiong Rhizoma including (Z)-ligustilide, butylphthalide, oleic acid, and myricetone were screened, which target 49 proteins including INS, BDNF, FOS, VEGFA, PTGS2, ESR1, MAPK14, and PTGS1. These proteins participated in 57 biological functions such as nuclear receptor activity, ligand activation, and transcription factor activity, involving 40 signaling pathways such as prolactin signaling pathway, breast cancer, and etrogen signaling. The results of molecular docking showed that myricetone, butylphthalide, 4-hydroxy-3 butylphthalide, (Z)-ligustilide, and ligustalide-E, among others, had strong affinities to 7 cores targets including BDNF, FOS, PTGS2, and MAPK14. In PC9 cells, treatment with Chuanxiong Rhizoma extract resulted in significant reductions in the phosphorylation levels of PI3K, Akt and VEGF (P<0.01). Conclusion Chuanxiong Rhizoma contains multiple active ingredients against brain metastasis lung cancer, and these ingredients act on multiple targets involving multiple signal pathways and biological functions.

Key words: Chuanxiong Rhizoma; network pharmacology; molecular docking; brain metastasis of lung cancer