基于网络药理学方法研究“黄芪–当归”药对治疗非小细胞肺癌的潜在机制
Study on the Potential Mechanisms of Huangqi-Danggui Drug Pair in the Treatment of Non-Small Cell Lung Cancer Based on Network Pharmacology Approach
DOI: 10.12677/TCM.2023.1210472, PDF,   
作者: 颜 乐：湖北中医药大学第一临床学院，湖北 武汉；张继先*：湖北省中西医结合医院呼吸与危重症医学科，湖北 武汉
关键词: 网络药理学；黄芪–当归；非小细胞肺癌(NSCLC)；作用机制；Network Pharmacology； Huangqi-Danggui (HQ-DG)； Non-Small Cell Lung Cancer (NSCLC)； Potential Mechanisms
摘要: 目的：通过网络药理学的方法探讨“黄芪–当归”药对治疗非小细胞肺癌(Non-Small Cell Lung Cancer, NSCLC)的潜在机制。方法：通过在线生物信息学工具获得黄芪–当归药对的活性成分和其相对应的靶点，以及NSCLC相关靶点，进而获得黄芪–当归药对与NSCLC的共有靶点，用以构建蛋白–蛋白相互作用(PPI)网络和筛选出核心靶点，并进行基因本体论(GO)分析和京都基因和基因组百科全书(KEGG)通路富集分析，最终建立药对–成分–靶点–通路网络。结果：筛选出黄芪–当归药对治疗NSCLC的主要活性成分和核心靶点。黄芪–当归药对治疗NSCLC的主要活性成分为槲皮素、紫花前胡醇当归酯和前胡素，其核心靶点为SRC、STAT3、AKT1、TP53、HSP90AA1、PIK3CA等。此外，黄芪–当归药对在NSCLC治疗中可能作用于PI3K/Akt和JAK/STAT信号通路。结论：黄芪–当归药对可能通过多成分、多靶点、多途径在NSCLC的治疗中发挥作用，为进一步的实验验证提供了思路与思考。
Abstract: Objective: This paper aims to study on the potential mechanisms of Huangqi-Danggui (HQ-DG) drug pair in the treatment of Non-Small Cell Lung Cancer (NSCLC) by methods of network pharmacology. Approach: Through online bioinformatics tools the active components of HQ-DG drug pair and their corresponding targets, as well as NSCLC related targets, were obtained, and then the common tar-gets of HQ-DG drug pair and NSCLC were obtained to construct protein-protein interaction (PPI) networks and screen out core targets, and perform gene ontology (GO) analysis and Kyoto Encyclo-pedia of Genes and Genomes (KEGG) pathway enrichment analysis to establish the drug-component-target-pathway network. Results: The capital active components and core targets of HQ-DG drug pair for the treatment of NSCLC were selected. The capital active components of HQ-DG drug pair for the treatment of NSCLC are quercetin, Decursinol angelate (DA), and Decursin (D); the core targets are SRC, STAT3, AKT1, TP53, HSP90AA1, PIK3CA and so on. Besides, HQ-DG drug pair is likely to act on PI3K/AKT signal pathway and JAK/STAT signal pathway in the treat-ment of NSCLC. Conclusion: The study indicates that HQ-DG drug pair might play a role in the treat-ment of NSCLC through multi-components, multi-targets, and multi-pathways, and provides ideas and thoughts for further experimental verification.
文章引用：颜乐, 张继先. 基于网络药理学方法研究“黄芪–当归”药对治疗非小细胞肺癌的潜在机制[J]. 中医学, 2023, 12(10): 3161-3174. https://doi.org/10.12677/TCM.2023.1210472

参考文献

[1] Sung, H., Ferlay, J., Siegel, R.L., et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71, 209-249. [Google Scholar] [CrossRef] [PubMed]
[2] Zhang, Q., Tang, L., Zhou, Y., He, W.B. and Li, W.M. (2021) Immune Checkpoint Inhibitor-Associated Pneumonitis in Non-Small Cell Lung Cancer: Current Understanding in Characteristics, Diagnosis, and Management. Frontiers in Immunology, 12, Article 663986. [Google Scholar] [CrossRef] [PubMed]
[3] Bodor, J.N., Boumber, Y. and Borghaei, H. (2020) Biomarkers for Immune Checkpoint Inhibition in Non-Small Cell Lung Cancer (NSCLC). Cancer, 126, 260-270. [Google Scholar] [CrossRef] [PubMed]
[4] Schabath, M.B. and Cote, M.L. (2019) Cancer Progress and Priorities: Lung Cancer. Cancer Epidemiology Biomarkers & Prevention, 28, 1563-1579. [Google Scholar] [CrossRef] 
[5] Yuan, M., Huang, L.L., Chen, J.H., Wu, J. and Xu, Q. (2019) The Emerging Treatment Landscape of Targeted Therapy in Non-Small-Cell Lung Cancer. Signal Transduction and Targeted Therapy, 4, Article No. 61. [Google Scholar] [CrossRef] [PubMed]
[6] Shokoohi, A., Al-Hashami, Z., Moore, S., et al. (2022) Effect of Targeted Therapy and Immunotherapy on Advanced Nonsmall-Cell Lung Cancer Outcomes in the Real World. Cancer Medicine, 11, 86-93. [Google Scholar] [CrossRef] [PubMed]
[7] Xiang, Y., Guo, Z., Zhu, P., Chen, J. and Huang, Y.Y. (2019) Traditional Chinese Medicine as a Cancer Treatment: Modern Perspectives of Ancient but Advanced Science. Cancer Medicine, 8, 1958-1975. [Google Scholar] [CrossRef] [PubMed]
[8] Zhang, L., Zhang, F.Y. and Li, G.F. (2021) Traditional Chinese Medicine and Lung Cancer—From Theory to Practice. Biomedicine & Pharmacotherapy, 137, Article ID: 111381. [Google Scholar] [CrossRef] [PubMed]
[9] 全建峰, 任革, 白小娜, 等. 中晚期非小细胞肺癌中医证型研究[J]. 河北中医药学报, 2016, 31(4): 11-14.
[10] 王文越, 王新蒙, 许丹丹, 等. 黄芪-当归药对配伍效用及其影响因素研究概况[J]. 中国中医基础医学杂志, 2023, 29(5): 865-870.
[11] 袁伟琛, 甄建华, 李晓红. 黄芪抗肿瘤作用的研究现状[J]. 中华中医药学刊, 2023, 41(6): 91-97.
[12] 马燕, 张育贵,石露萍, 等. 当归炮制品及其化学成分和药理作用研究进展[J]. 中国中药杂志: 1-10. 2023-07-19.[CrossRef] 
[13] 王雪振, 张小雨, 牟悦, 等. 当归补血汤在恶性肿瘤中作用的研究进展[J]. 中国实验方剂学杂志, 2022, 28(9): 214-220.
[14] Zhou, Z., Chen, B., Chen, S., et al. (2020) Applications of Network Pharmacology in Traditional Chinese Medicine Research. Evidence-Based Complementary and Alternative Medicine, 2020, Article ID: 1646905. [Google Scholar] [CrossRef] [PubMed]
[15] Guo, Q., Mao, X., Zhang, Y., et al. (2016) Guizhi-Shaoyao-Zhimu Decoction Attenuates Rheumatoid Arthritis Partially by Reversing Inflammation-Immune System Imbalance. Journal of Translational Medicine, 14, Article No. 165. [Google Scholar] [CrossRef] [PubMed]
[16] Wu, X.M. and Wu, C.F. (2015) Network Pharmacology: A New Approach to Unveiling Traditional Chinese Medicine. Chinese Journal of Natural Medicines, 13, 1-2. [Google Scholar] [CrossRef] 
[17] Ru, J., Li, P., Wang, J., et al. (2014) TCMSP: A Database of Systems Pharmacology for Drug Discovery from Herbal Medicines. Journal of Cheminformatics, 6, Article No. 13. [Google Scholar] [CrossRef] [PubMed]
[18] 李亚男, 荣小凤, 曹文富, 等. 黄芪抗肿瘤有效成分及作用机制研究进展[J]. 实用中医药杂志, 2017, 33(3): 341-343.
[19] 王常明, 姜睿斌, 李锋. 当归化学成分及抗肿瘤作用机制的研究进展[J]. 癌变∙畸变∙突变, 2019, 31(2): 162-165.
[20] 徐婷, 麦葭沂, 向俊, 等. “黄芪-当归”药对主要活性成分的网络药理学研究[J]. 中药材, 2017, 40(9): 2195-2201.
[21] Otasek, D., Morris, J.H., Bouças, J., Pico, A.R. and Demchak, B. (2019) Cytoscape Automation: Empowering Workflow- Based Network Analysis. Genome Biology, 20, Article No. 185. [Google Scholar] [CrossRef] [PubMed]
[22] Szklarczyk, D., Morris, J.H., Cook, H., et al. (2017) The STRING Database in 2017: Quality-Controlled Protein-Protein Association Networks, Made Broadly Accessible. Nucleic Acids Research, 45, D362-D368. [Google Scholar] [CrossRef] [PubMed]
[23] Chin, C.H., Chen, S.H., Wu, H.H., et al. (2014) cytoHubba: Identifying Hub Objects and Sub-Networks from Complex Interactome. BMC Systems Biology, 8, Article No. S11. [Google Scholar] [CrossRef] 
[24] Zhou, Y., Zhou, B., Pache, L., et al. (2019) Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets. Nature Communications, 10, Article No. 1523. [Google Scholar] [CrossRef] [PubMed]
[25] Herbst, R.S., Morgensztern, D. and Boshoff, C. (2018) The Biology and Management of Non-Small Cell Lung Cancer. Nature, 553, 446-454. [Google Scholar] [CrossRef] [PubMed]
[26] 唐于平, 束晓云, 李伟霞, 等. 药对研究(Ⅰ)——药对的形成与发展[J]. 中国中药杂志, 2013, 38(24): 4185-4190.
[27] Wu, T.H., Yeh, K.Y., Wang, C.H., et al. (2019) The Combination of Astragalus membranaceus and Angelica sinensis Inhibits Lung Cancer and Cachexia through Its Immunomodulatory Function. Journal of Oncology, 2019, Article ID: 9206951. [Google Scholar] [CrossRef] [PubMed]
[28] Rather, R.A. and Bhagat, M. (2020) Quercetin as an Innovative Therapeutic Tool for Cancer Chemoprevention: Molecular Mechanisms and Implications in Human Health. Cancer Medicine, 9, 9181-9192. [Google Scholar] [CrossRef] [PubMed]
[29] Klimaszewska-Wiśniewska, A., Hałas-Wiśniewska, M., et al. (2017) Antiproliferative and Antimetastatic Action of Quercetin on A549 Non-Small Cell Lung Cancer Cells through Its Effect on the Cytoskeleton. Acta Histochemica, 119, 99-112. [Google Scholar] [CrossRef] [PubMed]
[30] Lee, S.H., Lee, E.J., Min, K.H., et al. (2015) Quercetin Enhances Chemosensitivity to Gemcitabine in Lung Cancer Cells by Inhibiting Heat Shock Protein 70 Expression. Clinical Lung Cancer, 16, E235-E243. [Google Scholar] [CrossRef] [PubMed]
[31] Guo, H., Ding, H., Tang, X., et al. (2021) Quercetin Induces Pro-Apoptotic Autophagy via SIRT1/AMPK Signaling Pathway in Human Lung Cancer Cell Lines A549 and H1299 in vitro. Thoracic Cancer, 12, 1415-1422. [Google Scholar] [CrossRef] [PubMed]
[32] Lee, H.J., Lee, H.J., Lee, E.O., et al. (2009) In vivo Anti-Cancer Activity of Korean Angelica gigas and Its Major Pyranocoumarin Decursin. The American Journal of Chinese Medicine, 37, 127-142. [Google Scholar] [CrossRef] 
[33] Chang, S.N., Khan, I., Kim, C.G., et al. (2021) Decursinol Angelate Arrest Melanoma Cell Proliferation by Initiating Cell Death and Tumor Shrinkage via Induction of Apoptosis. International Journal of Molecular Sciences, 22, Article 4096. [Google Scholar] [CrossRef] [PubMed]
[34] Chang, S.N. and Kang, S.C. (2023) Decursinol Angelate Inhibits Glutamate Dehydrogenase 1 Activity and Induces Intrinsic Apoptosis in MDR-CRC Cells. Cancers, 15, Article 3541. [Google Scholar] [CrossRef] [PubMed]
[35] Jung, S.Y., Choi, J.H., Kwon, S.M., et al. (2012) Decursin Inhibits Vasculogenesis in Early Tumor Progression by Suppression of Endothelial Progenitor Cell Differentiation and Function. Journal of Cellular Biochemistry, 113, 1478-1487. [Google Scholar] [CrossRef] [PubMed]
[36] Choi, H.S., Cho, S.G., Kim, M.K., et al. (2016) Decursin in Angelica gigas Nakai (AGN) Enhances Doxorubicin Chemosensitivity in NCI/ADR-RES Ovarian Cancer Cells via Inhibition of P-Glycoprotein Expression. Phytotherapy Research, 30, 2020-2026. [Google Scholar] [CrossRef] [PubMed]
[37] Tošić, I. and Frank, D.A. (2021) STAT3 as a Mediator of Oncogenic Cellular Metabolism: Pathogenic and Therapeutic Implications. Neoplasia, 23, 1167-1178. [Google Scholar] [CrossRef] [PubMed]
[38] Zou, S., Tong, Q., Liu, B., et al. (2020) Targeting STAT3 in Cancer Immunotherapy. Molecular Cancer, 19, Article 145. [Google Scholar] [CrossRef] [PubMed]
[39] Yu, H. and Jove, R. (2004) The STATs of Cancer—New Molecular Targets Come of Age. Nature Reviews Cancer, 4, 97-105. [Google Scholar] [CrossRef] [PubMed]
[40] Zhang, J., Liu, X., Zhang, G., et al. (2023) To Explore the Effect of Kaempferol on Non-Small Cell Lung Cancer Based on Network Pharmacology and Molecular Docking. Frontiers in Pharmacology, 14, Article ID: 1148171. [Google Scholar] [CrossRef] [PubMed]
[41] Zhou, J., Sun, M., Jin, S., et al. (2019) Combined Using of Paclitaxel and Salinomycin Active Targeting Nanostructured Lipid Carriers against Non-Small Cell Lung Cancer and Cancer Stem Cells. Drug Delivery, 26, 281-289. [Google Scholar] [CrossRef] [PubMed]
[42] Wang, S., Liu, X., Zhou, T., et al. (2023) PKMYT1 Inhibits Lung Adenocarcinoma Progression by Abrogating AKT1 Activity. Cellular Oncology, 46, 195-209. [Google Scholar] [CrossRef] [PubMed]
[43] 孙肖, 毕经旺. PI3K抑制剂与非小细胞性肺癌[J]. 中国肿瘤生物治疗杂志, 2017, 24(5): 547-552.
[44] 宋忠花, 张金庆, 王言森. PIK3CA基因对人非小细胞肺癌A549细胞侵袭及迁移能力的影响[J]. 解剖科学进展, 2018, 24(3): 293-295.
[45] Pompura, S.L. and Dominguez-Villar, M. (2018) The PI3K/AKT Signaling Pathway in Regulatory T-Cell Development, Stability, and Function. Journal of Leukocyte Biology, 103, 1065-1076. [Google Scholar] [CrossRef] 
[46] Zhang, M. and Zhang, X. (2019) The Role of PI3K/AKT/FOXO Signaling in Psoriasis. Archives of Dermatological Research, 311, 83-91. [Google Scholar] [CrossRef] [PubMed]
[47] Jiang, N., Dai, Q., Su, X., et al. (2020) Role of PI3K/AKT Pathway in Cancer: The Framework of Malignant Behavior. Molecular Biology Reports, 47, 4587-4629. [Google Scholar] [CrossRef] [PubMed]
[48] Xue, C., Yao, Q., Gu, X., et al. (2023) Evolving Cognition of the JAK-STAT Signaling Pathway: Autoimmune Disorders and Cancer. Signal Transduction and Targeted Therapy, 8, Article No. 204. [Google Scholar] [CrossRef] [PubMed]
[49] Hu, X., Li, J., Fu, M., Zhao, X. and Wang, W. (2021) The JAK/STAT Signaling Pathway: From Bench to Clinic. Signal Transduction and Targeted Therapy, 6, Article No. 402. [Google Scholar] [CrossRef] [PubMed]
[50] Tzeng, H.T., Chyuan, I.T. and Lai, J.H. (2021) Targeting the JAK-STAT Pathway in Autoimmune Diseases and Cancers: A Focus on Molecular Mechanisms and Therapeutic Potential. Biochemical Pharmacology, 193, Article ID: 114760. [Google Scholar] [CrossRef] [PubMed]
[51] Villarino, A.V., Kanno, Y. and O’Shea, J.J. (2017) Mechanisms and Consequences of Jak-STAT Signaling in the Immune System. Nature Immunology, 18, 374-384. [Google Scholar] [CrossRef] [PubMed]