Network pharmacology‑based study to explore the mechanism of the Yiqi Gubiao pill in lung cancer treatment

Li,Zheng; Xu,Dan; Jing,Jing; Li,Fengsen

doi:10.3892/ol.2021.12583

Network pharmacology‑based study to explore the mechanism of the Yiqi Gubiao pill in lung cancer treatment

Authors:
- Zheng Li
- Dan Xu
- Jing Jing
- Fengsen Li
View Affiliations

Affiliations: Respiratory Department, The Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
Published online on: February 23, 2021 https://doi.org/10.3892/ol.2021.12583
Article Number: 321
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Lung cancer (LC) has been one of the most prevalent and fatal malignancies in the past 5 years. Yiqi Gubiao pills have a good clinical effect against LC. However, their complex composition limits proper understanding of their pharmacological mechanism. Therefore, the present study aimed to systemically explore the underlying mechanisms of Yiqi Gubiao pills in treatment of LC. The network pharmacology approach was employed to identify the active ingredients and LC targets associated with Yiqi Gubiao pills. Prediction of potential active ingredients and action targets was then conducted through protein‑protein interaction (PPI), Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. In vitro experiments were then performed to further verify the mechanism of action of Yiqi Gubiao pills, revealing that the anti‑LC effects were mediated by regulating the expression of IL6, TP53, albumin (ALB), MAPK3 and AKT1. In total, 102 active ingredients and 229 targets of Yiqi Gubiao pills were identified. The PPI network further revealed that AKT1, TP53, ALB, IL6 and MAPK3 were the top five hub genes associated with LC treatment. Targets of the Yiqi Gubiao pills were mainly enriched in the PI3K‑Akt and Advanced glycation end products (AGE)‑receptors for AGEs (RAGE) signaling pathways. Overall, network pharmacology deciphered the active ingredients and potential targets of the Yiqi Gubiao pills. Yiqi Gubiao pills partially inhibited the progression of LC by regulating the expression of hub genes (AKT1, TP53, ALB, IL6 and MAPK3) through the PI3K‑Akt and AGE‑RAGE signaling pathways. The findings of the present study may provide a theoretical basis for the clinical application of Yiqi Gubiao pills in LC treatment.

View Figures

View References

1	Mao Y, Yang D, He J and Krasna MJ: Epidemiology of lung cancer. Surg Oncol Clin N Am. 25:439–345. 2016. View Article : Google Scholar : PubMed/NCBI
2	Rivera GA and Wakelee H: Lung cancer in never smokers. Adv Exp Med Biol. 893:43–57. 2016. View Article : Google Scholar : PubMed/NCBI
3	Glinski K, Socha J, Wasilewska-Tesluk E, Komosinska K and Kepka L: Accelerated hypofractionated radiotherapy with concurrent full dose chemotherapy for locally advanced non-small cell lung cancer: A phase I/II study. Radiother Oncol. 148:174–180. 2020. View Article : Google Scholar : PubMed/NCBI
4	Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, Luesley D, Perren T, Bannoo S, Mascarenhas M, et al: Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): An open-label, randomised, controlled, non-inferiority trial. Lancet. 386:249–257. 2015. View Article : Google Scholar : PubMed/NCBI
5	Li FS, Zhang YL, Li Z, Xu D, Liao CY, Ma H, Gong L, Su J, Sun Q, Xu Q, et al: Randomized, double-blind, placebo-controlled superiority trial of the Yiqigubiao pill for the treatment of patients with chronic obstructive pulmonary disease at a stable stage. Exp Ther Med. 12:2477–2488. 2016. View Article : Google Scholar : PubMed/NCBI
6	Jiang L, Li F, Sun J, Huo H, Li X and Li H: Efficacy of Yiqigubiao pill on chronic obstructive pulmonary disease in rats with the disease induced by lipopolysaccharide and cigarette-smoke fumigation. J Tradit Chin Med. 40:983–991. 2020.PubMed/NCBI
7	Boezio B, Audouze K, Ducrot P and Taboureau O: Network-based approaches in pharmacology. Mol Inform. 36:2017. View Article : Google Scholar : PubMed/NCBI
8	Kibble M, Saarinen N, Tang J, Wennerberg K, Mäkelä S and Aittokallio T: Network pharmacology applications to map the unexplored target space and therapeutic potential of natural products. Nat Prod Rep. 32:1249–1266. 2015. View Article : Google Scholar : PubMed/NCBI
9	Wu Y, Zhang F, Yang K, Fang S, Bu D, Li H, Sun L, Hu H, Gao K, Wang W, et al: SymMap: An integrative database of traditional Chinese medicine enhanced by symptom mapping. Nucleic Acids Res. 47(D1): D1110–D1117. 2019. View Article : Google Scholar : PubMed/NCBI
10	Ye H, Ye L, Kang H, Zhang D, Tao L, Tang K, Liu X, Zhu R, Liu Q, Chen YZ, et al: HIT: Linking herbal active ingredients to targets. Nucleic Acids Res. 39((Database Issue)): D1055–D1059. 2011. View Article : Google Scholar : PubMed/NCBI
11	Keiser MJ, Roth BL, Armbruster BN, Ernsberger P, Irwin JJ and Shoichet BK: Relating protein pharmacology by ligand chemistry. Nat Biotechnol. 25:197–206. 2007. View Article : Google Scholar : PubMed/NCBI
12	Amberger JS, Bocchini CA, Schiettecatte F, Scott AF and Hamosh A: OMIM.org: Online mendelian inheritance in man (OMIM^®), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 43((Database Issue)): D789–D798. 2015. View Article : Google Scholar : PubMed/NCBI
13	Zhou J and Rudd KE: EcoGene 3.0. Nucleic Acids Res. 41((Database Issue)): D613–D624. 2013.PubMed/NCBI
14	The UniProt Consortium: UniProt: The universal protein knowledgebase. Nucleic Acids Res. 45(D1): D158–D169. 2017. View Article : Google Scholar : PubMed/NCBI
15	Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B and Ideker T: Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13:2498–2504. 2003. View Article : Google Scholar : PubMed/NCBI
16	The Gene Ontology Consortium: Expansion of the gene ontology knowledgebase and resources. Nucleic Acids Res. 45(D1): D331–D338. 2017. View Article : Google Scholar : PubMed/NCBI
17	Yu G, Wang LG, Han Y and He QY: clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS. 16:284–287. 2012. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Kang Y, Zhu X, Xu Y, Tang Q, Huang Z, Zhao Z, Lu J, Song G, Xu H, Deng C and Wang J: Energy stress-induced lncRNA HAND2-AS1 represses HIF1α-mediated energy metabolism and inhibits osteosarcoma progression. Am J Cancer Res. 8:526–537. 2018.PubMed/NCBI
20	Li S and Zhang B: Traditional Chinese medicine network pharmacology: Theory, methodology and application. Chin J Nat Med. 11:110–120. 2013. View Article : Google Scholar : PubMed/NCBI
21	Zhang R, Zhu X, Bai H and Ning K: Network pharmacology databases for traditional Chinese medicine: Review and assessment. Front Pharmacol. 10:1232019. View Article : Google Scholar : PubMed/NCBI
22	Zhang S, Ma Y, Hu X, Zheng Y and Chen X: Targeting PRMT5/Akt signalling axis prevents human lung cancer cell growth. J Cell Mol Med. 23:1333–1342. 2019. View Article : Google Scholar : PubMed/NCBI
23	Olivier M, Hollstein M and Hainaut P: TP53 mutations in human cancers: Origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2:a0010082010. View Article : Google Scholar : PubMed/NCBI
24	Zheng ZH, Wu DM, Fan SH, Zhang ZF, Chen GQ and Lu J: Upregulation of miR-675-5p induced by lncRNA H19 was associated with tumor progression and development by targeting tumor suppressor p53 in non-small cell lung cancer. J Cell Biochem. 120:18724–18735. 2019. View Article : Google Scholar : PubMed/NCBI
25	Du X, Shao Y, Qin HF, Tai YH and Gao HJ: ALK-rearrangement in non-small-cell lung cancer (NSCLC). Thorac Cancer. 9:423–430. 2018. View Article : Google Scholar : PubMed/NCBI
26	Wang J, Zhou Y, Ma L, Cao S, Gao W, Xiong Q, Wang K and Yang L: CIAPIN1 targeted NHE1 and ERK1/2 to suppress NSCLC Cells' metastasis and predicted good prognosis in NSCLC patients receiving pulmonectomy. Oxid Med Cell Longev. 2019:19708182019.PubMed/NCBI
27	Moncho-Amor V, Pintado-Berninches L, Ibañez de Cáceres I, Martín-Villar E, Quintanilla M, Chakravarty P, Cortes-Sempere M, Fernández-Varas B, Rodriguez-Antolín C, de Castro J, et al: Role of dusp6 phosphatase as a tumor suppressor in non-small cell lung cancer. Int J Mol Sci. 20:20362019. View Article : Google Scholar
28	Sun C, Li C, Li X, Zhu Y, Su Z, Wang X, He Q, Zheng G and Feng B: Scutellarin induces apoptosis and autophagy in NSCLC cells through ERK1/2 and AKT signaling pathways in vitro and in vivo. J Cancer. 9:3247–3256. 2018. View Article : Google Scholar : PubMed/NCBI
29	Tang H, Bai Y, Pan G, Wang X, Wei Y, Yang Z and Zhao J: Interleukin-6 and insulin-like growth factor-1 synergistically promote the progression of NSCLC. Autoimmunity. 51:399–407. 2018. View Article : Google Scholar : PubMed/NCBI
30	Xie Y, Shi X, Sheng K, Han G, Li W, Zhao Q, Jiang B, Feng J, Li J and Gu Y: PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol Med Rep. 19:783–791. 2019.PubMed/NCBI
31	Wu DM, Zhang T, Liu YB, Deng SH, Han R, Liu T, Li J and Xu Y: The PAX6-ZEB2 axis promotes metastasis and cisplatin resistance in non-small cell lung cancer through PI3K/AKT signaling. Cell Death Dis. 10:3492019. View Article : Google Scholar : PubMed/NCBI
32	Sparvero LJ, Asafu-Adjei D, Kang R, Tang D, Amin N, Im J, Rutledge R, Lin B, Amoscato AA, Zeh HJ and Lotze MT: RAGE (receptor for advanced glycation endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med. 7:172009. View Article : Google Scholar : PubMed/NCBI
33	Zeng T, Chen C, Yang P, Zuo W, Liu X and Zhang Y: A protective role for RHOJ in nonsmall cell lung cancer based on integrated bioinformatics analysis. J Comput Biol. 27:1092–1103. 2020. View Article : Google Scholar : PubMed/NCBI