Med Sci Monit Basic Res 26: e923431-1-e923431-10

Network Pharmacology to Uncover the Molecular Mechanisms of Action of LeiGongTeng for the Treatment of Nasopharyngeal Carcinoma

Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Radiation Oncology Clinical Medical Research Center of Guangxi, Nanning, Guangxi, P.R. China

^{Corresponding author.}

Corresponding Author: Ren-Sheng Wang, e-mail: moc.361@80060870831

^{Study Design}

^{Data Collection}

^{Statistical Analysis}

^{Data Interpretation}

^{Manuscript Preparation}

^{Literature Search}

^{Funds Collection}

^{Jing-Lin Mi and Chang Liu contributed equally to this work}

Received 2020 Feb 11; Accepted 2020 Mar 30.

This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

Abstract

Background

Nasopharyngeal carcinoma (NPC) is a common head and neck cancer epidemic in southern China and southeast Asia. LeiGongTeng has been widely used for the treatment of cancers. The purpose of this study was to determine the pharmacological mechanism of action of LeiGongTeng in the treatment of NPC using a network pharmacological approach.

Material/Methods

The traditional Chinese medicine systems pharmacology (TCMSP) database was used to identify active ingredients and associated target proteins for LeiGongTeng. Cytoscape was utilized to create a drug-disease network and topology analysis was conducted to analyze the degree of each ingredient. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) online tool was applied for the construction and analysis of the protein-protein interaction (PPI) network, while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and Gene Ontology (GO) functional analyses were utilized to determine drug-disease common genes.

Results

22 active ingredients including kaempferol, nobiletin, and beta-sitosterol, and 30 drug-disease common genes including VEGFA, CASP3, ESR1, and RELA were identified. GO analysis indicated that 94 biological processes, including RNA polymerase II, apoptotic process, response to drug, cell adhesion, and response to hypoxia, were found to be associated with NPC. The KEGG enrichment analysis showed that 58 pathways, including the PI3K-Akt signaling pathway, microRNAs in cancer, tumor necrosis factor (TNF) signaling pathway and pathways in cancer were found to be associated with NPC.

Conclusions

LeiGongTeng exerts its therapeutic effect through various biological processes and signaling pathways since it acts on several target genes. Systematic pharmacology can be used to predict the underlying function of LeiGongTeng and its mechanism of action in NPC.

MeSH Keywords: Medicine, Chinese Traditional; Nasopharyngeal Neoplasms; Pharmacologic Actions

Abstract

Footnotes

Source of support: This study was supported by the Basic Ability Enhancement Project of Young Teachers in Guangxi Zhuang Autonomous Region (No. 2018KY0134), Guangxi Science and Technology Cooperation and Exchange Project (GKH 159905-2-11), Central Guided Local Science and Technology Development Project (GK ZY18076006), and Guangxi Science and Technology Program Project (GK AD17129013)

Footnotes

References

1. Chen YP, Chan ATC, Le QT, et al Nasopharyngeal carcinoma. Lancet. 2019;394:64–80.[PubMed][Google Scholar]
2. Le QT, Colevas AD, O’Sullivan B, et al Current treatment landscape of nasopharyngeal carcinoma and potential trials evaluating the value of immunotherapy. J Natl Cancer Inst. :2019. [Epub ahead of print] [[PubMed][Google Scholar]
3. Tang LQ, Chen DP, Guo L, et al Concurrent chemoradiotherapy with nedaplatin versus cisplatin in stage II-IVB nasopharyngeal carcinoma: An open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2018;19:461–73.[PubMed][Google Scholar]
4. Lee AW, Ma BB, Ng WT, Chan ATManagement of nasopharyngeal carcinoma: current practice and future perspective. J Clin Oncol. 2015;33:3356–64.[PubMed][Google Scholar]
5. Frikha M, Auperin A, Tao Y, et al A randomized trial of induction docetaxel-cisplatin-5FU followed by concomitant cisplatin-RT versus concomitant cisplatin-RT in nasopharyngeal carcinoma (GORTEC 2006-02) Ann Oncol. 2018;29:731–36.[PubMed][Google Scholar]
6. Blanchard P, Lee A, Marguet S, et al Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol. 2015;16:645–55.[PubMed][Google Scholar]
7. Xu W, Towers AD, Li P, Collet JPTraditional Chinese medicine in cancer care: Perspectives and experiences of patients and professionals in China. Eur J Cancer Care. 2006;15:397–403.[PubMed][Google Scholar]
8. Qu Y, Zhang Z, Lu Y, et al Network pharmacology reveals the molecular mechanism of Cuyuxunxi prescription in promoting wound healing in patients with anal fistula. Evid Based Complement Alternat Med. 2019;2019 3865121. [Google Scholar]
9. Wong KF, Yuan Y, Luk JMTripterygium wilfordii bioactive compounds as anticancer and anti-inflammatory agents. Clin Exp Pharmacol Physiol. 2012;39:311–20.[PubMed][Google Scholar]
10. Law SK, Simmons MP, Techen N, et al Molecular analyses of the Chinese herb Leigongteng (Tripterygium wilfordii Hook.f.) Phytochemistry. 2011;72:21–26.[PubMed][Google Scholar]
11. Liu Z, Ma L, Zhou GBThe main anticancer bullets of the Chinese medicinal herb, thunder god vine. Molecules. 2011;16:5283–97.[Google Scholar]
12. Corson TW, Crews CMMolecular understanding and modern application of traditional medicines: Triumphs and trials. Cell. 2007;130:769–74.[Google Scholar]
13. Zhou H, Liu Y, Wang C, et al Triptolide inhibits Epstein-Barr nuclear antigen 1 expression by increasing sensitivity of mitochondria apoptosis of nasopharyngeal carcinoma cells. J Exp Clin Cancer Res. 2018;37:192.[Google Scholar]
14. Wang X, Zhang JJ, Sun YM, et al Triptolide induces apoptosis and synergizes with cisplatin in cisplatin-resistant HNE1/DDP nasopharyngeal cancer cells. Folia Biol (Praha) 2015;61:195–202.[PubMed][Google Scholar]
15. Zhang W, Kang M, Zhang T, et al Triptolide combined with radiotherapy for the treatment of nasopharyngeal carcinoma via NF-κB-related mechanism. Int J Mol Sci. 2016;17(12):2139.[Google Scholar]
16. Hopkins ALNetwork pharmacology: The next paradigm in drug discovery. Nat Chem Biol. 2008;4:682–90.[PubMed][Google Scholar]
17. He R, Ou S, Chen S, Ding SNetwork pharmacology-based study on the molecular biological mechanism of action for Compound Kushen Injection in anti-cancer effect. Med Sci Monit. 2020;26:e918520.[Google Scholar]
18. Yang L, Liu W, Hu Z, et al A systems pharmacology approach for identifying the multiple mechanisms of action of the Wei Pi Xiao decoction for the treatment of gastric precancerous lesions. Evid Based Complement Alternat Med. 2019;2019 1562707. [Google Scholar]
19. Ru J, Li P, Wang J, et al TCMSP: A database of systems pharmacology for drug discovery from herbal medicines. J Cheminformatics. 2014;6:13.[Google Scholar]
20. Safran M, Chalifa-Caspi V, Shmueli O, et al Human Gene-Centric Databases at the Weizmann Institute of Science: GeneCards, UDB, CroW 21 and HORDE. Nucleic Acids Res. 2003;31:142–46.[Google Scholar]
21. Amberger JS, Bocchini CA, Schiettecatte F, et al OMIM.org: Online Mendelian Inheritance in Man (OMIM^{), an online catalog of human genes and genetic disorders.}Nucleic Acids Res. 2015;43:D789–98.[Google Scholar]
22. Su G, Morris JH, Demchak B, Bader GDBiological network exploration with Cytoscape 3. Curr Protoc Bioinformatics. 2014;47:8.13.1–24.[Google Scholar]
23. Szklarczyk D, Franceschini A, Wyder S, et al STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447–52.[Google Scholar]
24. Ashburner M, Ball CA, Blake JA, et al. Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25–29.
25. Kanehisa M, Sato Y, Kawashima M, et al KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 2016;44:D457–62.[Google Scholar]
26. Huang DW, Sherman BT, Lempicki RASystematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.[PubMed][Google Scholar]
27. Fang W, Yang Y, Ma Y, et al Camrelizumab (SHR-1210) alone or in combination with gemcitabine plus cisplatin for nasopharyngeal carcinoma: Results from two single-arm, phase 1 trials. Lancet Oncol. 2018;19:1338–50.[PubMed][Google Scholar]
28. Zhang Y, Chen L, Hu GQ, et al Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma. N Engl J Med. 2019;381:1124–35.[PubMed][Google Scholar]
29. Chan AT, Grégoire V, Lefebvre JL, et al Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(Suppl 7):vii83–85.[PubMed][Google Scholar]
30. Wang SS, Lv Y, Xu XC, et al Triptonide inhibits human nasopharyngeal carcinoma cell growth via disrupting Lnc-RNA THOR-IGF2BP1 signaling. Cancer Lett. 2019;443:13–24.[PubMed][Google Scholar]
31. Hsieh MJ, Wang CW, Lin JT, et al Celastrol, a plant-derived triterpene, induces cisplatin-resistance nasopharyngeal carcinoma cancer cell apoptosis though ERK1/2 and p38 MAPK signaling pathway. Phytomedicine. 2019;58:152805.[PubMed][Google Scholar]
32. Yoshida T, Konishi M, Horinaka M, et al Kaempferol sensitizes colon cancer cells to TRAIL-induced apoptosis. Biochem Biophys Res Commun. 2008;375:129–33.[PubMed][Google Scholar]
33. Chen AY, Chen YCA review of the dietary flavonoid, kaempferol on human health and cancer chemoprevention. Food Chem. 2013;138:2099–107.[Google Scholar]
34. Ma X, Jin S, Zhang Y, et al Inhibitory effects of nobiletin on hepatocellular carcinoma in vitro and in vivo. Phytother Res. 2014;28:560–67.[PubMed][Google Scholar]
35. Awad AB, Chinnam M, Fink CS, Bradford PGBeta-sitosterol activates Fas signaling in human breast cancer cells. Phytomedicine. 2007;14:747–54.[PubMed][Google Scholar]
36. Ye Z, Wang F, Yan F, et al Identification of candidate genes of nasopharyngeal carcinoma by bioinformatical analysis. Arch Oral Biol. 2019;106:104478.[PubMed][Google Scholar]
37. Huang D, Song SJ, Wu ZZ, et al Epstein-Barr virus-induced VEGF and GM-CSF drive nasopharyngeal carcinoma metastasis via recruitment and activation of macrophages. Cancer Res. 2017;77:3591–604.[PubMed][Google Scholar]
38. Xueguan L, Xiaoshen W, Yongsheng Z, et al Hypoxia inducible factor-1 alpha and vascular endothelial growth factor expression are associated with a poor prognosis in patients with nasopharyngeal carcinoma receiving radiotherapy with carbogen and nicotinamide. Clin Oncol (R Coll Radiol) 2008;20:606–12.[PubMed][Google Scholar]
39. Zhang Z, Yu X, Guo Y, et al Genetic variant in CASP3 affects promoter activity and risk of esophageal squamous cell carcinoma. Cancer Sci. 2012;103:555–60.[PubMed][Google Scholar]
40. Chen K, Zhao H, Hu Z, et al CASP3 polymorphisms and risk of squamous cell carcinoma of the head and neck. Clin Cancer Res. 2008;14:6343–49.[Google Scholar]
41. Sun H, Deng Q, Pan Y, et al Association between estrogen receptor 1 (ESR1) genetic variations and cancer risk: A meta-analysis. J BUON. 2015;20:296–308.[PubMed][Google Scholar]
42. Ooft ML, van Ipenburg J, van Loo R, et al Molecular profile of nasopharyngeal carcinoma: analysing tumour suppressor gene promoter hypermethylation by multiplex ligation-dependent probe amplification. J Clin Pathol. 2018;71:351–59.[PubMed][Google Scholar]
43. Lung HL, Kan R, Chau WY, et al The anti-tumor function of the IKK inhibitor PS1145 and high levels of p65 and KLF4 are associated with the drug resistance in nasopharyngeal carcinoma cells. Sci Rep. 2019;9:12064.[Google Scholar]
44. Wang J, Deng L, Huang J, et al High expression of Fibronectin 1 suppresses apoptosis through the NF-κB pathway and is associated with migration in nasopharyngeal carcinoma. Am J Transl Res. 2017;9:4502–11.[Google Scholar]
45. Young RARNA polymerase II. Annu Rev Biochem. 1991;60:689–715.[PubMed][Google Scholar]
46. Takacs M, Segesdi J, Banati F, et al The importance of epigenetic alterations in the development of Epstein-Barr virus-related lymphomas. Mediterr J Hematol Infect Dis. 2009;1:e2009012.[Google Scholar]
47. Tan BJ, Tan BH, Chiu GNEffect of triptolide on focal adhesion kinase and survival in MCF-7 breast cancer cells. Oncol Rep. 2011;26:1315–21.[PubMed][Google Scholar]
48. Rankin EB, Giaccia AJThe role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ. 2008;15:678–85.[Google Scholar]
49. Zhou ZL, Luo ZG, Yu B, et al Increased accumulation of hypoxia-inducible factor-1α with reduced transcriptional activity mediates the antitumor effect of triptolide. Mol Cancer. 2010;9:268.[Google Scholar]
50. Sethi G, Sung B, Aggarwal BBTNF: A master switch for inflammation to cancer. Front Biosci. 2008;13:5094–107.[PubMed][Google Scholar]
51. Yu Y, Ke L, Xia WX, et al Elevated Levels of TNF-α and decreased levels of CD68-positive macrophages in primary tumor tissues are unfavorable for the survival of patients with nasopharyngeal carcinoma. Technol Cancer Res Treat. 2019;18 1078142455. [Google Scholar]
52. Esquela-Kerscher A, Slack FJOncomirs – microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–69.[PubMed][Google Scholar]
53. Luo J, Manning BD, Cantley LCTargeting the PI3K-Akt pathway in human cancer: Rationale and promise. Cancer Cell. 2003;4:257–62.[PubMed][Google Scholar]
54. Wang M, Chen B, Chai LTriptolide suppresses the proliferation and induces the apoptosis of nasopharyngeal carcinoma cells via the PI3K/Akt pathway. Oncol Lett. 2019;17:1372–78.[Google Scholar]