A Network Pharmacology Approach for Uncovering the Antitumor Effects and Potential Mechanisms of the Sijunzi Decoction for the Treatment of Gastric Cancer

Abstract

Background. Sijunzi decoction (SJZD), a classic Chinese formula, has been clinically used for the treatment of gastrointestinal disorders. However, few studies have uncovered its antitumor effects and its potential mechanisms against gastric cancer (GC). Therefore, this work aimed to identify the active compounds and putative targets of the SJZD and to further explore the potential mechanisms involved in the treatment of GC. Materials and Methods. The active compounds and potential targets of the SJZD and related genes for GC treatment were collected from a public database. Traditional Chinese medicine (TCM)-compound-target-disease networks, Venn diagrams, protein–protein interactions (PPIs), gene ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to obtain the bioactive compounds, key targets, and potential pathways. Next, the human gastric adenocarcinoma cell line NUGC-4 was inoculated subcutaneously into the right flank of NCG mice to build a tumor-bearing mouse model to further verify the findings. Results. There were 117 compounds in the SJZD in total. The SJZD and GC had 161 and 3288 potential targets, respectively, among which 123 targets overlapped. The network analysis showed that quercetin, kaempferol formononetin, ginsenoside, atractylenolide III, etc., were bioactive molecules. The tumor necrosis factor (TNF), interleukin-6 (IL-6), cellular tumor antigen p53 (TP53), transcription factor AP-1 (JUN), and vascular endothelial growth factor A (VEGFA) were potential targets. A KEGG pathway enrichment analysis revealed 110 pathways involved in the pathways for cancer, including the PI3K-AKT signaling pathway. Validation experiments showed that the SJZD inhibited tumor growth and induced apoptosis in tumor cells. In addition, the SJZD downregulated expressions of VEGFA, iNOS, COX-2, and Bax/Bcl2 and inhibited the expressions of p-PI3K and p-AKT. Conclusion. The SJZD treats GC by inhibiting blood vessel hyperplasia and inducing cell apoptosis by regulating the PI3K/AKT pathway.

Clinical Efficacy and Gut Microbiota Regulating-Related Effect of Si-Jun-Zi Decoction in Postoperative Non-Small Cell Lung Cancer Patients: A Prospective Observational Study

“…Numerous studies have indicated that SJZD exhibits an anti-cancer efficacy as well as a synergistic effect in preventing cancer cachexia, alleviating inflammatory response, improving malnutrition state, and enhancing QOL. 23 , 24 , 46 - 48 …”

Chinese herbal medicine combined with oxaliplatin-based chemotherapy for advanced gastric cancer: A systematic review and meta-analysis of contributions of specific medicinal materials to tumor response

“…Among them, four herbs constitute a typical formula in China, Sijunzi decoction, which has been shown to reduce the nuclear accumulation and DNA-binding activity of β-catenin, thereby repressing cell growth and inducing apoptosis in human GC MKN74 and MKN45 cells ( Li et al, 2021 ). Network pharmacology and experimental validation suggested that Sijunzi decoction could inhibit tumor proliferation and angiogenesis by down-regulating the expression of VEGFA, iNOS, COX-2, and Bax/Bcl2 proteins in NCG-bearing mice with human gastric adenocarcinoma cell NUGC-4, regulate the PI3K/AKT pathway, and induce apoptosis ( Ding et al, 2022 ). To further explore how seven herbs improve the short-term efficacy of platinum-based chemotherapy for AGC, we will review each herb to assess the mechanistic evidence of the specific anti-tumor activity.…”

Research progress of ginseng in the treatment of gastrointestinal cancers

“…In addition, one study reported that ginseng diol induced apoptosis in the pancreatic cancer cell lines PANC-1 and Patu8988 through the JAK2/STAT3 signaling pathway, limiting the progression of pancreatic cancer ( Fan et al, 2021 ). Ding et al observed that Sijunzi tang, with GS as one of the main components, downregulates the expression of VEGFA, iNOS, COX-2 and Bax/Bcl2, regulates the PI3K/AKT pathway, and induces apoptosis to treat gastric cancer cells NUGC-4 ( Ding et al, 2022 ). (24r)-Ginsenoside HQ (R-PHQ) and (24s)-Ginsenoside HQ (S-PHQ) are the main metabolites of (20s)-Ginsenoside Rh₂ (GRh₂) in vivo .…”