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Systematic insight into the active constituents and mechanism of Guiqi Baizhu for the treatment of gastric cancer.

ABSTRACT: Traditional Chinese medicine treatment of diseases has been recognized, but the material basis and mechanisms are not clear. In this study, target prediction of the antigastric cancer (GC) effect of Guiqi Baizhu (GQBZP) and the analysis of potential key compounds, key targets, and key pathways for the therapeutic effects against GC were carried out based on the method of network analysis and Kyoto Encyclopedia of Genes and Genomes enrichment. There were 33 proteins shared between GQBZP and GC, and 131 compounds of GQBZP had a high correlation with these proteins, indicating that the PI3K-AKT signaling pathway might play a key role in GC. From these studies, we selected human epidermal growth factor receptor 2 (HER2) and programmed cell death 1-ligand 1 (PD-L1) for docking; the results showed that 385 and 189 compounds had high docking scores with HER2 and PD-L1, respectively. Six compounds were selected for microscale thermophoresis (MST). Daidzein/quercetin and isorhamnetin/formononetin had the highest binding affinity for HER2 and PD-L1, with K_d values of 3.7 μmol/L and 490, 667, and 355 nmol/L, respectively. Molecular dynamics simulation studies based on the docking complex structures as the initial conformation yielded the binding free energy between daidzein/quercetin with HER2 and isorhamnetin/formononetin with PD-L1, calculated by molecular mechanics Poisson-Boltzmann surface area, of -26.55, -14.18, -19.41, and -11.86 kcal/mol, respectively, and were consistent with the MST results. In vitro experiments showed that quercetin, daidzein, and isorhamnetin had potential antiproliferative effects in MKN-45 cells. Enzyme activity assays showed that quercetin could inhibit the activity of HER2 with an IC₅₀ of 570.07 nmol/L. Our study provides a systematic investigation to explain the material basis and molecular mechanism of traditional Chinese medicine in treating diseases.

SUBMITTER: Li L

PROVIDER: S-EPMC8088928 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveThis study aimed to investigate the possible mechanism of the Zhishi and Baizhu herb pair in the treatment of gastric cancer by means of network pharmacology and molecular docking and to provide a theoretical basis for experiments and clinical application of traditional Chinese medicine for treating gastric cancer.MethodsThe main active chemical components of Zhishi and Baizhu were screened through Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and selected by using the thresholds of oral bioavailability ≥30% and drug-likeness ≥18%. The targets of Zhishi and Baizhu were obtained from TCMSP, Therapeutic Targets Database (TTD), and the DrugBank database. The corresponding genes of the targets were retrieved from the UniProt database, and the gastric cancer targets were obtained from the GeneCards database and TTD. Subsequently, the networks were built between the main drug components, drug targets, and gastric cancer targets. Then, the enrichment analyses of GO and KEGG were applied to predict the potential roles of gastric cancer pathogenesis via the R package clusterProfiler. Finally, molecular docking was used to determine the affinity between the targets and components.ResultsTwenty-seven main active components were predicted from the Zhishi-Baizhu herb pair, and a total of 120 intersection genes were screened from 303 potential medicine genes and 1,839 disease genes. The enrichment included the PI3K-Akt and IL-17 signaling pathways, and the network analysis showed that the Zhishi-Baizhu herb pair acted on seven key targets, namely, AKT1, MMP9, IL-6, CCND1, BCL2, MTOR, and MDM2 (where they played a role in treating gastric cancer). Molecular docking showed that luteolin and naringenin could stably bind to the targets.ConclusionThe possible mechanisms of the components of the Zhishi-Baizhu herb pair in treating gastric cancer might be related to luteolin and naringenin, which intervened with the targets AKT1, MMP9, IL-6, CCND1, BCL2, MTOR, and MDM2, and are linked with the PI3K-Akt and IL-17 signaling pathways. This knowledge will lay a solid foundation for further experimental and clinical studies.

Project description:BackgroundSurgery is the main treatment option for patients with local gastric cancer. However, surgery alone is usually not sufficient for stomach cancer patients, and combined therapies are recommended for these patients. In recent studies, some preoperative treatments have shown benefits. However, the treatment selection is still uncertain because previous studies failed to obtain a statistically significant difference between preoperative chemotherapy and preoperative chemoradiotherapy. Therefore, we plan to perform a systematic review and meta-analysis to compare the benefits among these preoperative treatments.Methods/designThis review includes randomized controlled trials with or without blinding as well as published studies, high-quality unpublished studies, full articles and meeting abstracts with an English context if sufficient results were provided for analysis. Data sources include the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, major relevant international conferences and manual screening of references. Patients with a diagnosis of resectable primary gastric or EGJ adenocarcinoma (stage II or higher) who underwent surgery alone or preoperative treatment followed by surgery and who were pathologically confirmed as proposed by the AJCC 2017 guidelines without age, sex, race, subtypes of adenocarcinoma and molecular pathology limitations will be included. The following three interventions will be included: surgery alone, neoadjuvant chemistry followed by surgery and neoadjuvant chemoradiotherapy followed by surgery. All-cause mortality, overall survival (OS, the time interval from diagnosis to death) and/or progression-free survival (PFS, the time interval from diagnosis to disease progression or death from any cause) will be defined as major results of concern. The clinical and pathological response rate (according to RECIST and tumour regression score), R0 resection rate, quality of life and grade 3 or above adverse events (according to the National Cancer Institute Common Terminology Criteria for Adverse Events, NCI-CTCAE) will be defined as the secondary outcomes.DiscussionThe aim of this systematic review is to compare the benefits of different preoperative treatments for patients with locoregional stomach cancer. This systematic review will improve the understanding of the relative efficacy of these treatment options by providing the latest evidence on the efficacy of various treatment options in the management of gastric cancer patients and may guide clinical practice.Systematic review registrationPROSPERO CRD4202123718.

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Systematic insight into the active constituents and mechanism of Guiqi Baizhu for the treatment of gastric cancer.

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