Network pharmacology and molecular docking reveal the mechanism of action of Bergapten against non‑small cell lung cancer

Chen,Yihao; Fu,Yu; Zou,Hongbo; Wang,Pingsong; Xu,Yao; Xie,Qichao

doi:10.3892/ol.2024.14833

Network pharmacology and molecular docking reveal the mechanism of action of Bergapten against non‑small cell lung cancer

Authors:
- Yihao Chen
- Yu Fu
- Hongbo Zou
- Pingsong Wang
- Yao Xu
- Qichao Xie
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Affiliations: Department of Oncology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing 401120, P.R. China
Published online on: December 4, 2024 https://doi.org/10.3892/ol.2024.14833
Article Number: 87
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Non‑small cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide, necessitating new treatment approaches with minimal side effects. In the present study, the potential of Bergapten (5‑methoxypsoralen), a natural furanocoumarin compound, as a therapeutic agent against NSCLC was investigated by using network pharmacology, molecular docking and in vitro validation. Bergapten targets were identified using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and SwissTarget databases, whilst lung cancer‑related targets were sourced from GeneCards and DisGeNET. Protein‑protein interaction analysis and molecular docking were performed to identify key targets. The inhibitory effects of Bergapten on lung cancer cells were assessed using Cell Counting Kit‑8 assays, wound healing assays, cell migration experiments, flow cytometry and western blotting. SC79 was used to verify the regulation of Bergapten on the PI3K/AKT pathway. Network pharmacology identified 51 targets, one signaling pathway and four Gene Ontology projects associated with the action of Bergapten against NSCLC. Key targets identified included glycogen synthase kinase‑3β, Janus kinase 2, phosphatidylinositol‑4,5‑bisphosphate 3‑kinase, catalytic subunit α and protein tyrosine kinase 2. In vitro experiments demonstrated that Bergapten significantly inhibited cell viability, promoted apoptosis, induced cellular senescence and inhibited the PI3K/AKT signaling pathway in NSCLC cells. In conclusion, Bergapten exerts its anti‑NSCLC effects through the PI3K/AKT pathway, promoting cell senescence and inhibiting inflammation. These findings suggest that Bergapten has potential as a therapeutic agent for NSCLC.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
2	Pakzad R, Mohammadian-Hafshejani A, Ghoncheh M, Pakzad I and Salehiniya H: The incidence and mortality of lung cancer and their relationship to development in Asia. Transl Lung Cancer Res. 4:763–774. 2015.PubMed/NCBI
3	Amini A, Byers LA, Welsh JW and Komaki RU: Progress in the management of limited-stage small cell lung cancer. Cancer. 120:790–798. 2014. View Article : Google Scholar : PubMed/NCBI
4	Liu Y, Ao X, Yu W, Zhang Y and Wang J: Biogenesis, functions, and clinical implications of circular RNAs in non-small cell lung cancer. Mol Ther Nucleic Acids. 27:50–72. 2021. View Article : Google Scholar : PubMed/NCBI
5	American Cancer Society: Cancer Facts & Figures 2024. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2024-cancer-facts-figures.htmlOctober 22–2024
6	Liang Y, Xie L, Liu K, Cao Y, Dai X, Wang X, Lu J, Zhang X and Li X: Bergapten: A review of its pharmacology, pharmacokinetics, and toxicity. Phytother Res. 35:6131–6147. 2021. View Article : Google Scholar : PubMed/NCBI
7	Luo TT, Lu Y, Yan SK, Xiao X, Rong XL and Guo J: Network pharmacology in research of chinese medicine formula: Methodology, application and prospective. Chin J Integr Med. 26:72–80. 2020. View Article : Google Scholar : PubMed/NCBI
8	Zhou Z, Chen B, Chen S, Lin M, Chen Y, Jin S, Chen W and Zhang Y: Applications of network pharmacology in traditional Chinese medicine research. Evid Based Complement Alternat Med. 2020:16469052020. View Article : Google Scholar : PubMed/NCBI
9	Peng Y, Wang Y, Zhou C, Mei W and Zeng C: PI3K/Akt/mTOR pathway and its role in cancer therapeutics: Are we making headway? Front Oncol. 12:8191282022. View Article : Google Scholar : PubMed/NCBI
10	Eberhardt J, Santos-Martins D, Tillack AF and Forli S: AutoDock Vina 1.2.0: New docking methods, expanded force field, and python bindings. J Chem Inf Model. 61:3891–3898. 2021. View Article : Google Scholar : PubMed/NCBI
11	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
12	Gautschi O, Ratschiller D, Gugger M, Betticher DC and Heighway J: Cyclin D1 in non-small cell lung cancer: A key driver of malignant transformation. Lung Cancer. 55:1–14. 2007. View Article : Google Scholar : PubMed/NCBI
13	Siegfried JM, Hershberger PA and Stabile LP: Estrogen receptor signaling in lung cancer. Semin Oncol. 36:524–531. 2009. View Article : Google Scholar : PubMed/NCBI
14	Alves M, Borges DP, Kimberly A, Martins Neto F, Oliveira AC, de Sousa JC, Nogueira CD, Carneiro BA and Tavora F: Glycogen synthase kinase-3 beta expression correlates with worse overall survival in non-small cell lung cancer-A clinicopathological series. Front Oncol. 11:6210502021. View Article : Google Scholar : PubMed/NCBI
15	Sun Y, Moretti L, Giacalone NJ, Schleicher S, Speirs CK, Carbone DP and Lu B: Inhibition of JAK2 signaling by TG101209 enhances radiotherapy in lung cancer models. J Thorac Oncol. 6:699–706. 2011. View Article : Google Scholar : PubMed/NCBI
16	Chen W, Li Z, Bai L and Lin Y: NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target. Front Biosci (Landmark Ed). 16:1172–1185. 2011. View Article : Google Scholar : PubMed/NCBI
17	Wang Y, Wang Y, Li J, Li J and Che G: Clinical significance of PIK3CA gene in non-small-cell lung cancer: A systematic review and meta-analysis. Biomed Res Int. 2020:36082412020.PubMed/NCBI
18	Tong X, Tanino R, Sun R, Tsubata Y, Okimoto T, Takechi M and Isobe T: Protein tyrosine kinase 2: A novel therapeutic target to overcome acquired EGFR-TKI resistance in non-small cell lung cancer. Respir Res. 20:2702019. View Article : Google Scholar : PubMed/NCBI
19	Hoden B, DeRubeis D, Martinez-Moczygemba M, Ramos KS and Zhang D: Understanding the role of Toll-like receptors in lung cancer immunity and immunotherapy. Front Immunol. 13:10334832022. View Article : Google Scholar : PubMed/NCBI
20	Payea MJ, Anerillas C, Tharakan R and Gorospe M: Translational control during cellular senescence. Mol Cell Biol. 41:e00512–20. 2021. View Article : Google Scholar : PubMed/NCBI
21	Jo H, Mondal S, Tan D, Nagata E, Takizawa S, Sharma AK, Hou Q, Shanmugasundaram K, Prasad A, Tung JK, et al: Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death. Proc Natl Acad Sci USA. 109:10581–10586. 2012. View Article : Google Scholar : PubMed/NCBI
22	Manning BD and Toker A: AKT/PKB signaling: Navigating the network. Cell. 169:381–405. 2017. View Article : Google Scholar : PubMed/NCBI
23	Maidarti M, Anderson RA and Telfer EE: Crosstalk between PTEN/PI3K/Akt signalling and DNA damage in the oocyte: Implications for primordial follicle activation, oocyte quality and ageing. Cells. 9:2002020. View Article : Google Scholar : PubMed/NCBI
24	Oh SJ, Erb HHH, Hobisch A, Santer FR and Culig Z: Sorafenib decreases proliferation and induces apoptosis of prostate cancer cells by inhibition of the androgen receptor and Akt signaling pathways. Endocr Relat Cancer. 19:305–319. 2012. View Article : Google Scholar : PubMed/NCBI
25	Reuter S, Eifes S, Dicato M, Aggarwal BB and Diederich M: Modulation of anti-apoptotic and survival pathways by curcumin as a strategy to induce apoptosis in cancer cells. Biochem Pharmacol. 76:1340–1351. 2008. View Article : Google Scholar : PubMed/NCBI
26	Kowald A, Passos JF and Kirkwood TBL: On the evolution of cellular senescence. Aging Cell. 19:e132702020. View Article : Google Scholar : PubMed/NCBI
27	Wiley CD and Campisi J: The metabolic roots of senescence: Mechanisms and opportunities for intervention. Nat Metab. 3:1290–1301. 2021. View Article : Google Scholar : PubMed/NCBI
28	Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M and Alimonti A: Cellular senescence: Aging, cancer, and injury. Physiol Rev. 99:1047–1078. 2019. View Article : Google Scholar : PubMed/NCBI
29	Salama R, Sadaie M, Hoare M and Narita M: Cellular senescence and its effector programs. Genes Dev. 28:99–114. 2014. View Article : Google Scholar : PubMed/NCBI
30	Tesei A, Arienti C, Bossi G, Santi S, De Santis I, Bevilacqua A, Zanoni M, Pignatta S, Cortesi M, Zamagni A, et al: TP53 drives abscopal effect by secretion of senescence-associated molecular signals in non-small cell lung cancer. J Exp Clin Cancer Res. 40:892021. View Article : Google Scholar : PubMed/NCBI
31	Lv FZ, Wang JL, Wu Y, Chen HF and Shen XY: Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells. Int J Immunopathol Pharmacol. 28:77–84. 2015. View Article : Google Scholar : PubMed/NCBI
32	Liu C, Yang L, Xu H, Zheng S, Wang Z, Wang S, Yang Y, Zhang S, Feng X, Sun N, et al: Systematic analysis of IL-6 as a predictive biomarker and desensitizer of immunotherapy responses in patients with non-small cell lung cancer. BMC Med. 20:1872022. View Article : Google Scholar : PubMed/NCBI
33	Li C, Zheng H, Xiong J, Huang Y, Li H, Jin H, Ai S, Wang Y, Su T, Sun G, et al: miR-596-3p suppresses brain metastasis of non-small cell lung cancer by modulating YAP1 and IL-8. Cell Death Dis. 13:6992022. View Article : Google Scholar : PubMed/NCBI
34	Hashimoto K, Nishimura S and Akagi M: Lung adenocarcinoma presenting as a soft tissue metastasis to the shoulder: A case report. Medicina (Kaunas). 57:1812021. View Article : Google Scholar : PubMed/NCBI
35	Liu C, Qin Q and Cong H: Research progress on the relationship between mitochondrial deoxyguanosine kinase and apoptosis and autophagy in lung adenocarcinoma cells. Cancer Insight. 1:53–62. 2022. View Article : Google Scholar