Study on the mechanism of Baishao Qiwu Decoction in the treatment of colorectal cancer based on network pharmacology and molecular docking

doi:10.5246/jcps.2023.01.002

Abstract

Abstract:

In the present study, we investigated the mechanism of Baishao Qiwu Decotion (BSQWD) in the treatment of colorectal cancer (CRC) based on network pharmacology and molecular docking technology. The active components and all targets of traditional Chinese medicine (TCM) were screened by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and the compositive target network diagram was drawn by Cytoscape software. Potential CRC targets were identified by GeneCards, OMIM, PharmGKB, TTD, and DrugBank databases. Cytoscape was used to integrate chemical components, targets, and diseases in BSQWD. The STRING platform line protein-protein interaction (PPI) analysis was performed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) analyses were performed using R language. Finally, AutoDock and SYBYL-X 2.0 were used to perform molecular docking. The results showed that seven kinds of medicinal materials in BSQWD contained 110 chemical components. There were 9048 CRC-related genes. BSQWD was associated with 184 target genes. Hub genes were identified, which were JUN, HSP90AA1, TP53, AKT1, and TNF. Moreover, 2589 GO items were enriched, including 2324 biological processes, 67 cell components, and 198 molecular functions. KEGG analysis obtained 179 pathways. The molecular docking results showed that the potentially active ingredients, cynaropicrin and rivularin, had good binding with the hub genes HSP90AA1 and TP53. Collectively, the reaseach showed that BSQWD achieved the anti-CRC mechanism through the synergistic regulation of multiple components, multiple targets, and multiple pathways, providing a theoretical basis and scientific basis for the application of BSQWD.

Key words: Baishao Qiwu Decoction, Colorectal cancer, Network pharmacology, Molecular docking

Supporting:

Ning Ding, Tao Zhang, Ji Luo, Haochen Liu, Yu Deng, Yongheng He. Study on the mechanism of Baishao Qiwu Decoction in the treatment of colorectal cancer based on network pharmacology and molecular docking[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(1): 17-31.

Figures/Tables 11

Table 1. Active compounds in BSQWD.

Table 2. Information of key components in the top 10 of the Degree.

References 48

[1]	Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424.
[2]	Chen, W.Q.; Li, N.; Lan, P. Chinese Guidelines for Colorectal Cancer Screening, Early Diagnosis and Early Treatment (2020, Beijing). Chin. J. Oncol. 2021, 30, 1–28.
[3]	Robertson, D.J.; Ladabaum, U. Opportunities and challenges in moving from current guidelines to personalized colorectal cancer screening. Gastroenterology. 2019, 156, 904–917.
[4]	Wen, X.L.; Cheng, H.B. Discussion on treating of metastasis of colorectal cancer by pathogenesis theory of cancer toxin. China J. Tradit. Chin. Med. Pharm. 2021, 36, 6497–6499.
[5]	Sun, Q.; He, M.; Zhang, M.; Zeng, S.; Chen, L.; Zhao, H.; Yang, H.; Liu, M.L.; Ren, S.; Xu, H.B. Traditional Chinese medicine and colorectal cancer: implications for drug discovery. Front. Pharmacol. 2021, 12, 685002.
[6]	Lin, M.S.; Yang, S.J. Research progress on traditional Chinese medicine in the treatment of colorectal cancer. Guangming J. Chin. Med. 2020, 35, 2270–2272.
[7]	Song, X.P. Clinical observation of Shaoyao Decoction combined with conventional chemotherapy in treating advanced colorectal carcinoma. China’s Naturopathy. 2020, 28, 74–76.
[8]	Wang, X.Y.; Saud, S.M.; Zhang, X.W.; Li, W.D.; Hua, B.J. Protective effect of Shaoyao Decoction against colorectal cancer via the Keap1-Nrf2-ARE signaling pathway. J. Ethnopharmacol. 2019, 241, 111981.
[9]	Nogales, C.; Mamdouh, Z.M.; List, M.; Kiel, C.; Casas, A.I.; Schmidt, H.H.H.W. Network pharmacology: curing causal mechanisms instead of treating symptoms. Trends Pharmacol. Sci. 2022, 43, 136–150.
[10]	Luo, T.T.; Lu, Y.; Yan, S.K.; Xiao, X.; Rong, X.L.; Guo, J. Network pharmacology in research of Chinese medicine formula: methodology, application and prospective. Chin. J. Integr. Med. 2020, 26, 72–80.
[11]	Ru, J.L.; Li, P.; Wang, J.N.; Zhou, W.; Li, B.H.; Huang, C.; Li, P.D.; Guo, Z.H.; Tao, W.Y.; Yang, Y.F.; Xu, X.; Li, Y.; Wang, Y.H.; Yang, L. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J. Cheminform. 2014, 6, 13.
[12]	UniProt Consortium. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res. 2021, 49, D480–D489.
[13]	Otasek, D.; Morris, J.H.; Bouças, J.; Pico, A.R.; Demchak, B. Cytoscape Automation: empowering workflow-based network analysis. Genome Biol. 2019, 20, 185.
[14]	Safran, M.; Dalah, I.; Alexander, J.; Rosen, N.; Iny Stein, T.; Shmoish, M.; Nativ, N.; Bahir, I.; Doniger, T.; Krug, H.; Sirota-Madi, A.; Olender, T.; Golan, Y.; Stelzer, G.; Harel, A.; Lancet, D. GeneCards Version 3: the human gene integrator. Database (Oxford). 2010, 2010, baq020.
[15]	Hamosh, A.; Amberger, J.S.; Bocchini, C.; Scott, A.F.; Rasmussen, S.A. Online Mendelian inheritance in man (OMIM®): victor McKusick’s magnum opus. Am. J. Med. Genet. A. 2021, 185, 3259–3265.
[16]	Whirl-Carrillo, M.; McDonagh, E.M.; Hebert, J.M.; Gong, L.; Sangkuhl, K.; Thorn, C.F.; Altman, R.B.; Klein, T.E. Pharmacogenomics knowledge for personalized medicine. Clin. Pharmacol. Ther. 2012, 92, 414–417.
[17]	Zhou, Y.; Zhang, Y.T.; Lian, X.C.; Li, F.C.; Wang, C.X.; Zhu, F.; Qiu, Y.Q.; Chen, Y.Z. Therapeutic target database update 2022: facilitating drug discovery with enriched comparative data of targeted agents. Nucleic Acids Res. 2021, 50, D1398–D1407.
[18]	Law, V.; Knox, C.; Djoumbou, Y.; Jewison, T.; Guo, A.C.; Liu, Y.F.; Maciejewski, A.; Arndt, D.; Wilson, M.; Neveu, V.; Tang, A.; Gabriel, G.; Ly, C.; Adamjee, S.; Dame, Z.T.; Han, B.; Zhou, Y.; Wishart, D.S. DrugBank 4.0: shedding new light on drug metabolism. Nucleic Acids Res. 2013, 42, D1091–D1097.
[19]	Otasek, D.; Morris, J.H.; Bouças, J.; Pico, A.R.; Demchak, B. Cytoscape Automation: empowering workflow-based network analysis. Genome Biol. 2019, 20, 185.
[20]	Szklarczyk, D.; Gable, A.L.; Nastou, K.C.; Lyon, D.; Kirsch, R.; Pyysalo, S.; Doncheva, N.T.; Legeay, M.; Fang, T.; Bork, P.; Jensen, L.J.; von Mering, C. The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res. 2020, 49, D605–D612.
[21]	Minoru, K.; Miho, F.; Mao, T.; Yoko, S.; Kanae, M. KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017, 45, D353–D361.
[22]	Kim, S.; Cheng, T.J.; He, S.Q.; Thiessen, P.A.; Li, Q.L.; Gindulyte, A.; Bolton, E.E. PubChem protein, gene, pathway, and taxonomy data collections: bridging biology and chemistry through target-centric views of PubChem data. J. Mol. Biol. 2022, 434, 167514.
[23]	Burley, S.K.; Bhikadiya, C.; Bi, C.X.; Bittrich, S.; Chen, L.; Crichlow, G.V.; Christie, C.H.; Dalenberg, K.; di Costanzo, L.; Duarte, J.M.; Dutta, S.; Feng, Z.K.; Ganesan, S.; Goodsell, D.S.; Ghosh, S.; Green, R.K.; Guranović, V.; Guzenko, D.; Hudson, B.P.; Lawson, C.L.; Liang, Y.H.; Lowe, R.; Namkoong, H.; Peisach, E.; Persikova, I.; Randle, C.; Rose, A.; Rose, Y.; Sali, A.; Segura, J.; Sekharan, M.; Shao, C.H.; Tao, Y.P.; Voigt, M.; Westbrook, J.D.; Young, J.Y.; Zardecki, C.; Zhuravleva, M. RCSB Protein Data Bank: powerful new tools for exploring 3D structures of biological macromolecules for basic and applied research and education in fundamental biology, biomedicine, biotechnology, bioengineering and energy sciences. Nucleic Acids Res. 2020, 49, D437–D451.
[24]	Pan, Z.H. Research progress of traditional Chinese medicine in treating colorectal cancer in recent ten years. Acta Chin. Med. Pharmacol. 1996, 24, 16–17.
[25]	Zhao, M.M.; Gao, M.; Tian, Y.L.; Du, Y.F.; Wang, C.Y.; Xu, H.J.; Zhang, L.T.; Wang, Q. Pharmacokinetic and tissue distribution studies of paeoniflorin and albiflorin in rats after oral administration of total glycosides of paeony by HPLC-MS/MS. J. Chin. Pharm. Sci. 2014, 23, 403–411.
[26]	Luo, X.P.; Yu, Z.L.; Yue, B.; Ren, J.Y.; Zhang, J.; Mani, S.; Wang, Z.T.; Dou, W. Obacunone reduces inflammatory signalling and tumour occurrence in mice with chronic inflammation-induced colorectal cancer. Pharm. Biol. 2020, 58, 886–897.
[27]	Wang, H.Y.; Yu, H.Z.; Zheng, Y.L.. Research progress of anti-tumor effect of berberine. Chin. Tradit. Pat. Med. 2015, 37, 1791–1795.
[28]	Lu, X.H.; Zhang, J.J.; Liang, H.; Zhao, Y.Y. Chemical constituents of angelica sinensis. J. Chin. Pharm. Sci. 2004, 13, 1–3.
[29]	Jiao, Y.H.; Sun, S.H.; Xin, M.; Xu, J.J.; Jiang, J.J.; Jia, X.Q. New progress in the anti-tumor action of Scutellaria baicalensis Georgi and its active ingredients. Glob. Tradit. Chin. Med. 2021, 14, 1159–1165.
[30]	Elsebai, M.F.; Mocan, A.; Atanasov, A.G. Cynaropicrin: a comprehensive research review and therapeutic potential As an anti-hepatitis C virus agent. Front. Pharmacol. 2016, 7, 472.
[31]	Liu, T.Y. Cynaropicrin targeting thioredoxin reductase as a promising anti-cancer agent. LanZhou University. 2019.
[32]	Zheng, D.D.; Zhu, Y.; Shen, Y.L.; Xiao, S.S.; Yang, L.H.; Xiang, Y.Q.; Dai, X.X.; Hu, W.L.; Zhou, B.; Liu, Z.G.; Zhao, H.Y.; Zhao, C.G.; Huang, X.Y.; Wang, L.X. Cynaropicrin shows antitumor progression potential in colorectal cancer through mediation of the LIFR/STATs axis. Front. Cell Dev. Biol. 2021, 8, 605184.
[33]	Ponte, L.; Pavan, I.; Mancini, M.; Silva, L.; Morelli, A.; Severino, M.; Bezerra, R.; Simabuco, F. The hallmarks of flavonoids in cancer. Molecules. 2021, 26, 2029.
[34]	Cui, M.Y.; Lu, A.R.; Li, J.X.; Liu, J.; Fang, Y.M.; Pei, T.L.; Zhong, X.; Wei, Y.K.; Kong, Y.; Qiu, W.Q.; Hu, Y.H.; Yang, J.; Chen, X.Y.; Martin, C.; Zhao, Q. Two types of O-methyltransferase are involved in biosynthesis of anticancer methoxylated 4´-deoxyflavones in Scutellaria baicalensis Georgi. Plant Biotechnol. J. 2021, 20, 129–142.
[35]	Liu, L.; Wu, S.H.; Li, Y.Y.; Xu, X.Y.; He, S.; Wen, F.F.; Guo, N.J.; Jia, Z.Z. Correlation of HSF1, c-Jun and DPD expression in colorectal adenocarcinoma and their clinical significance. Chin. J. Clin. Exp. Pathol. 2020, 36, 1261–1268.
[36]	Zuehlke, A.D.; Beebe, K.; Neckers, L.; Prince, T. Regulation and function of the human HSP90AA1 gene. Gene. 2015, 570, 8–16.
[37]	Yun, C.W.; Kim, H.J.; Lim, J.H.; Lee, S.H. Heat shock proteins: agents of cancer development and therapeutic targets in anti-cancer therapy. Cells. 2019, 9, 60.
[38]	Chen, E.F.; Yang, F.F.; He, H.J.; Li, Q.Q.; Zhang, W.; Xing, J.L.; Zhu, Z.Q.; Jiang, J.J.; Wang, H.; Zhao, X.J.; Liu, R.T.; Lei, L.; Dong, J.; Pei, Y.C.; Yang, Y.; Pan, J.Q.; Zhang, P.; Liu, S.Z.; Du, L.; Zeng, Y.; Yang, J. Alteration of tumor suppressor BMP5 in sporadic colorectal cancer: a genomic and transcriptomic profiling based study. Mol. Cancer. 2018, 17, 176.
[39]	Zhao, X.J.; Liu, J.Z.; Liu, S.Z.; Yang, F.F.; Chen, E.F. Construction and validation of an immune-related prognostic model based on TP53 status in colorectal cancer. Cancers. 2019, 11, 1722.
[40]	Xu, X.; Yao, D.Y. Expression and clinical significance of Girdin and Akt1 in colorectal carcinoma. Hebei Med. J. 2016, 38, 2259–2261, 2266.
[41]	Dostert, C.; Grusdat, M.; Letellier, E.; Brenner, D. The TNF family of ligands and receptors: communication modules in the immune system and beyond. Physiol. Rev. 2019, 99, 115–160.
[42]	Xu, H.; Liu, T.; Li, J.; Chen, F.; Xu, J.; Hu, L.; Jiang, L.; Xiang, Z.; Wang, X.; Sheng, J. Roburic acid targets TNF to inhibit the NF-κB signaling pathway and suppress human colorectal cancer cell growth. Front. Immunol. 2022, 13, 853165.
[43]	Yang, X.L.; Sun, X.M.; Zhao, X.H.; Yang, L.J.; Shen, W.G.; Xiao, Z.S.; Guo, C.; Liu, Y.B. Expressions of IL-17E, IL-17F and their receptors in colorectal carcinoma tissue and their significances. J. Jilin Univ. Med. Ed. 2018, 44, 574–578, 696.
[44]	Guo, Y.J.; Pan, W.W.; Liu, S.B.; Shen, Z.F.; Xu, Y.; Hu, L.L. ERK/MAPK signalling pathway and tumorigenesis. Exp. Ther. Med. 2020, 19, 1997–2007.
[45]	Fang, J.Y.; Richardson, B.C. The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 2005, 6, 322–327.
[46]	Yang, Y.; Xia, D.Q.; Wang, W. Effects of inhibitor PD98059 blocking MAPK/ERK pathway on inhibiting proliferation and promoting apoptosis of colorectal cancer cells. J. Colorectal. Anal. Surg. 2019, 25, 657–667.
[47]	Moradi-Marjaneh, R.; Hassanian, S.M.; Fiuji, H.; Soleimanpour, S.; Ferns, G.; Avan, A.; Khazaei, M. Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer. J. Cell Physiol. 2018, 233, 5613–5622.
[48]	Ren, Y.M.; Fang, J.Y. Toll-likereceptorfamily-relatedsignalingpathwayanditsrelationship with colorectal cancer. Tumor. 2019, 39, 589–594.