广东工业大学学报 ›› 2022, Vol. 39 ›› Issue (04): 98-106.doi: 10.12052/gdutxb.210148

• • 上一篇    下一篇

基于网络药理学和分子对接技术的百合地黄汤抗肝癌作用机制研究

何燕1, 张紫菱1, 招彦彤1, 黎晓静1, 魏梅2   

  1. 1. 广东工业大学 生物医药学院, 广东 广州 510006;
    2. 广东一方制药有限公司 广东省中药配方颗粒企业重点实验室, 广东 佛山 528244
  • 收稿日期:2021-10-12 出版日期:2022-07-10 发布日期:2022-06-29
  • 通信作者: 魏梅(1967–)，女，主任药师，主要研究方向为新药开发，E-mail：weimei67@126.com
  • 作者简介:何燕(1979–)，女，副教授，博士，主要研究方向为中药制剂及中药新药，E-mail：heyan129@gdut.edu.cn
  • 基金资助:
    广东省科技创新“攀登计划”资助项目(pdjh2020b0187)

A Study of the Mechanism of Baihe Dihuang Decoction in the Treatment of Hepatocellular Carcinoma Based on Network Pharmacology and Molecular Docking

He Yan1, Zhang Zi-ling1, Zhao Yan-tong1, Li Xiao-jing1, Wei Mei2   

  1. 1. School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;
    2. Guangdong Key Laboratory of Traditional Chinese Medicine Formula Granule, Guangdong Yifang Pharmaceutical Co., Ltd., Foshan 528244, China
  • Received:2021-10-12 Online:2022-07-10 Published:2022-06-29

HTML

PDF (PC)

1994

摘要： 中医药是我国肝癌患者综合治疗方案的重要组成部分之一，本文基于网络药理学和分子对接技术探讨经典名方百合地黄汤治疗肝癌的作用机制。通过TCMSP数据库和文献挖掘百合地黄汤的化学成分，借助SwissTargetPrediction数据库预测其作用靶点，经Uniprot数据库将靶点蛋白名称标准化。从OMIM、GeneCards数据库获取肝癌的有效治疗靶点。取百合地黄汤作用靶点与肝癌靶点制作韦恩图，运用String数据库结合Cytoscape3.7.2软件对百合地黄汤抗肝癌的潜在作用靶点作蛋白相互作用网络，构建“药物−化学成分−作用靶点”和“药物−活性成分−抗肝癌靶点”网络图。利用David平台对百合地黄汤抗肝癌潜在作用靶点进行GO(基因本体)和KEGG(京都基因与基因组)富集分析。运用Autodock Vina软件对百合地黄汤的主要活性成分与核心作用靶点进行分子对接验证。收集得到百合地黄汤131个化学成分，主要活性成分有山奈酚、百合皂苷、百合苷C等，共得到58个百合地黄汤抗肝癌靶点。蛋白−蛋白相互作用(Protein-Protein Interaction, PPI)网络计算出主要有STAT3、CASP3、VEGFA等关键靶点。富集分析得到91条信号通路，涉及癌症蛋白聚糖、VEGF信号通路、PI3K-Akt信号通路等。分子对接结果表明百合地黄汤与肝癌蛋白靶点具有较好的亲和性。百合地黄汤通过多成分、多靶点、多通路抑制肿瘤细胞增殖，促进肿瘤细胞凋亡来治疗肝癌。

关键词: 百合地黄汤, 网络药理学, 分子对接, 肝癌

Abstract: Traditional Chinese medicine is an important part of the comprehensive treatment of hepatocellular carcinoma (HCC) patients in China. To explore the potential mechanism of Baihe Dihuang Decoction in the treatment of hepatocellular carcinoma, the network pharmacology and molecular docking was used. Excavating the ingredient of each drug in Baihe Dihuang Decoction used TCMSP database and literature, and its target protein was predicted by the Swiss Target Prediction database. Disease targets relating to hepatocellular carcinoma were screened out through OMIM and Gene Cards databases, and the target protein name was standardized by the UniProt database. The drug targets and disease targets were selected to make a Veen diagram. PPI network of potential targets was constructed using STRING platform combined with Cytoscape3.7.2 software, and GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Gene and Genomes) pathways data were obtained to conduct enrichment analysis and predict its mechanism of action. One hundred thirty-one chemical components of Baihe Dihuang Decoction were collected. And the main active components included kaempferol, brownioside and lilioside C. 58 targets of Baihe Dihuang Decoction for the treatment of hepatocellular carcinoma were selected. The PPI network showed the key targets were STAT3, CASP3, VEGFA. The enrichment analysis of KEGG screened out 91 signaling pathways including cancer proteoglycan, VEGF signaling pathway, and PI3K Akt signaling pathway. The results of molecular docking showed that the main active components in Baihe Dihuang Decoction had a stable binding activity with core targets. The compounds in Baihe Dihuang Decoction can play a therapeutic role in the treatment of HCC by acting on multiple targets and multiple pathways to inhibit the proliferation of tumor cells and promote the apoptosis of tumor cells.

Key words: Baihe Dihuang Decoction, network pharmacology, molecular docking, hepatocellular carcinoma

中图分类号: 

  • R285
[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. A Cancer Journal for Clinicians, 2021, 71(3): 209-249.
[2] 孟唤男, 赵丽, 刘柳, 等. 中西医结合防治原发性肝癌研究进展[J]. 中医药学报, 2021, 49(2): 115-119.
MENG H N, ZHAO L, LIU L, et al. Research progress on prevention and treatment of primary liver cancer by traditional Chinese and western medicine [J]. Acta Chinese Medicine and Pharmacology, 2021, 49(2): 115-119.
[3] 赵智强, 吴勉华, 赵延华. 论恶性肿瘤中医辨治体系的建立[J]. 中医杂志, 2015, 56(11): 906-908.
ZHAO Z Q, WU M H, ZHAO Y H. Establishing the system of TCM syndrome differentiation and treatment in malignant tumors [J]. Journal of Traditional Chinese Medicine, 2015, 56(11): 906-908.
[4] 中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版)[J]. 中国实用外科杂志, 2020, 40(2): 121-138.
Bureau of Medical Administration, Nationsl Health Commission of the People’s Republic of China. Standardization for diagnosis and treatment of primary hepatic carcinom (2019 edition) [J]. Chinese Journal of Practical Surgery, 2020, 40(2): 121-138.
[5] 张仲景. 新编金匮要略方论[M]. 北京: 商务印书馆, 1955: 46-47.
[6] 范希然, 李多多, 许刚, 等. 百合地黄汤的历史沿革研究[J]. 世界中医药, 2020, 15(23): 3660-3664.
FAN X R, LI D D, XU G, et al. Study on the historical evolution of Baihe Dihuang Decoction [J]. World Chinese Medicine, 2020, 15(23): 3660-3664.
[7] 包素珍, 郑小伟, 宋 红, 等. 百合地黄汤对肝癌H22荷瘤小鼠抑瘤作用的实验研究[J]. 中国中医药科技, 2006, 13(5): 332.
[8] 黄建波, 郑小伟, 包素珍. 加味百合地黄汤对Lewis肺癌小鼠抗肿瘤转移作用机制的研究[J]. 现代中西医结合杂志, 2006, 15(23): 3187-3189.
HUANG J B, ZHENG X W, BAO S Z. Anti tumor metastasis action mechanism study of Baihe Dihuang Decoction with additives on mice with Lewis lung cancer [J]. Modern Journal of Integrated Traditional Chinese and Western Medicine, 2006, 15(23): 3187-3189.
[9] 王伯阳, 刘天龙, 刘晶, 等. 基于网络药理学筛选的黄芪香草酸对心肌重构的保护作用研究[J]. 中国中药杂志, 2020, 45(2): 367-373.
WANG B Y, LIU T L, LIU J, et al. Study on protective effect of vanillic acid from Astragalus membranaceus on hypertensive cardiac remodeling based on network pharmacology screen [J]. China Journal of Chinese Materia Medica, 2020, 45(2): 367-373.
[10] 罗虹, 刘博文, 杨慧, 等. 基于网络药理学及活性成分测定的六味地黄系列制剂质量研究[J]. 中草药, 2020, 51(21): 5462-5477.
LUO H, LIU B W, YANG H, et al. Quality study on Liuwei Dihuang series preparations via network pharmacology and active ingredient determination [J]. Chinese Traditional and Herbal Drugs, 2020, 51(21): 5462-5477.
[11] 罗雪菲, 王伟, 赵晓芳, 等. 基于网络药理学探讨桃莲绞复方增强全成分肿瘤细胞疫苗抗结直肠癌作用分子机制[J]. 中草药, 2021, 52(2): 459-468.
LUO X F, WANG W, ZHAO X F, et al. Molecular mechanism of Tao-lian-jiao Formula (TLF) to enhance anti-colorectaltumor activity of whole tumor cell vaccine based on network pharmacology [J]. Chinese Traditional and Herbal Drugs, 2021, 52(2): 459-468.
[12] 任艳, 邓燕君, 马焓彬, 等. 网络药理学在中药领域的研究进展及面临的挑战[J]. 中草药, 2020, 51(18): 4789-4797.
REN Y, DENG Y J, MA H B, et al. Research progress and challenges of network pharmacology in field of traditional Chinese medicine [J]. Chinese Traditional and Herbal Drugs, 2020, 51(18): 4789-4797.
[13] 孟凡翠, 汤立达. 中药网络药理学研究中存在的问题与发展展望[J]. 中草药, 2020, 51(8): 2232-2237.
MENG F C, TANG L D. Challenges and prospect in research of Chinese materia medica network pharmacology [J]. Chinese Traditional and Herbal Drugs, 2020, 51(8): 2232-2237.
[14] RU J, LI P, WANG J, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines [J]. Journal of Cheminformatics, 2014, 6(1): 13.
[15] WANG Y, XIAO J, SUZEK T O, et al. PubChem's BioAssay database [J]. Nucleic Acids Research, 2012, 40(D1): 400-412.
[16] DAINA A, MICHIELIN O, ZOETE V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules[J]. Scientific Reports, 2017, 7, 42717.
[17] GFELLER D, GROSDIDIER A, WIRTH M, et al. SwissTarget Prediction: a web server for target prediction of bioactive small molecules [J]. Nucleic Acids Research, 2014, 42(W1): W32-W38.
[18] RENDE D, BAYSAL N, KIRDAR B. Integration of cardiovascular disease protein interaction network and OMIM database [J]. New Biotechnology, 2009, 25: S345.
[19] MICHAEL R, VERED C, JAIME P, et al. Gene Cards: integrating information about genes, proteins and diseases [J]. Trends in Genetics, 1997, 13(4): 163.
[20] 罗静初. UniProt蛋白质数据库简介[J]. 生物信息学, 2019, 17(3): 131-144.
LUO J C. A brief introduction to UniProt [J]. Chinese Journal of Bioinformatics, 2019, 17(3): 131-144.
[21] SHANNON P. Cytoscape: a software environment for integrated models of biomolecular interaction networks [J]. Genome Research, 2003, 13(11): 2498-2504.
[22] DENNIS G, SHERMAN B T, HOSACK D A, et al. DAVID: database for annotation, visualization, and integrated discovery [J]. Genome Biology, 2003, 4: P3(2003).
[23] OLEG T, ARTHUR J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading [J]. Journal of Computational Chemistry, 2010, 31(2): 455-461.
[24] 赵蕾, 武嫣斐, 高耀, 等. 基于网络药理学的百合地黄汤干预心理亚健康作用机制研究[J]. 药学学报, 2017, 52(1): 99-105.
ZHAO L, WU Y F, GAO Y, et al. Intervention mechanism of psychological sub-health by Baihe Dihuang Tang based on network pharmacology [J]. Acta Pharmaceutica Sinica, 2017, 52(1): 99-105.
[25] 梁爱华, 薛宝云, 王金华, 等. 鲜地黄与干地黄止血和免疫作用比较研究[J]. 中国中药杂志, 1999, 24(11): 663-666.
LIANG A H, XUE B Y, WANG J H, et al. A study on hemostatic and immunological actions of fresh and dry Dihuang [J]. China Journal of Chinese Materia Medica, 1999, 24(11): 663-666.
[26] LI H J, LI H Y. Ginsenoside-Rg5 inhibits growth and metastasis of ovarian carcinoma via suppressing expression of fibroblast growth factor-8b (FGF8b) [J]. Journal of King Saud University Science, 2020, 32(1): 1162-1167.
[27] 申宏, 马佳乐, 赵智圆, 等. 中医药干预相关信号通路防治肝癌研究进展[J]. 国际中医中药杂志, 2021, 43(1): 93-97.
SHEN H, MA J L, ZHAO Z Y, et al. Research progress on the prevention and treatment of liver cancer intervened by Traditional Chinese Medicine on related signaling pathway [J]. International Journal of Traditional Chinese Medicine, 2021, 43(1): 93-97.
[28] 雷晓青, 陈鳌, 刘毅, 等. 山萘酚药理作用的研究进展[J]. 微量元素与健康研究, 2017, 34(2): 61-62.
[29] YUAN J, ZHANG F, NIU R. Multiple regulation pathways and pivotal biological functions of STAT3 in cancer [J]. Science Reports, 2015, 5: 17663.
[30] YU H, LEE H, HERRMANN A, et al. Revisiting STAT3 signaling in cancer: new and unexpected biological functions [J]. Nature Reviews Cancer, 2014, 14(11): 736-746.
[31] GEIGER J, GRANDIS J, BAUMAN J. The STAT3 pathway as a therapeutic target in head and neck cancer: barriers and innovations [J]. Oral Oncology, 2016, 56: 84-92.
[32] ARMAN K, ERGUN S, TEMIZ E, et al. The interrelationship between HER2 and CASP3/8 with apoptosis in different cancer cell lines [J]. Molecular Biology Reports, 2014, 41(12): 8031-8036.
[33] FOLKMAN J. Tumor angiogenesis: therapeutic implications [J]. The New England Journal of Medicine, 1971, 285(21): 1182-1186.
[34] 李晓蕊, 郭青龙, 卢娜. VEGFA/VEGFR2作用于血管内皮细胞途径及其抑制剂研究进展[J]. 药物生物技术, 2016, 23(3): 274-278.
LI X R, GUO Q L, LU N. Researching progress in the pathway acting on vascular endothelial cells of VEGFR2 and its signaling inhibitors [J]. Pharmaceutical Biotechnology, 2016, 23(3): 274-278.
[35] BOURGUIGNON L. Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression [J]. Seminars in Cancer Biology, 2008, 18(4): 251-259.
[36] NAPOLEONE F, HANS-PETER G, JENNIFER L. The biology of VEGF and its receptors [J]. Nature Medicine, 2003, 9(6): 669-676.
[37] ZOU Y, LEI W, SU S, et al. Chlamydia trachomatis plasmid-encoded protein Pgp3 inhibits apoptosis via the PI3K-AKT-mediated MDM2-p53 axis [J]. Molecular and Cellular Biochemistry, 2019, 452(1-2): 167-176.
[1] 罗俊, 刘丹, 丁利君. 二氢杨梅素的检测、药效及药代学研究进展[J]. 广东工业大学学报, 2020, 37(03): 88-94.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
版权所有 © 2017 《广东工业大学学报》编辑部
地址：广州市东风东路729号广东工业大学 邮编：510090
电话：020-37626653,020-37626139,020-37626396
邮箱：xbzrb@gdut.edu.cn
本系统由北京玛格泰克科技发展有限公司设计开发