基于网络药理学方法揭示四君子汤治疗胃癌的抗肿瘤作用及潜在机制
A Network Pharmacology Approach for Uncovering the Antitumor Effects and Potential Mechanisms of the Sijunzi Decoction for the Treatment of Gastric Cancer.
作者信息
Ding Pengpeng, Guo Yutong, Wang Canghai, Chen Jianhong, Guo Chunmei, Liu Hong, Shi Qi
机构信息
Department of Gastroenterology, Beijing Shijitan Hospital of Capital Medical University, Beijing 100038, China.
Ophthalmoptometry Class, Fourth Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu 210000, China.
出版信息
Evid Based Complement Alternat Med. 2022 Apr 12;2022:9364313. doi: 10.1155/2022/9364313. eCollection 2022.
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.
背景
四君子汤（SJZD）是一种经典的中药方剂，临床上已用于治疗胃肠道疾病。然而，很少有研究揭示其抗肿瘤作用及其对胃癌（GC）的潜在机制。因此，本研究旨在确定SJZD的活性成分和潜在靶点，并进一步探索其治疗GC的潜在机制。
材料与方法
从公共数据库中收集SJZD的活性成分、潜在靶点以及与GC治疗相关的基因。利用中药-化合物-靶点-疾病网络、维恩图、蛋白质-蛋白质相互作用（PPI）、基因本体论（GO）和京都基因与基因组百科全书（KEGG）来获取生物活性化合物、关键靶点和潜在途径。接下来，将人胃腺癌细胞系NUGC-4皮下接种到NCG小鼠的右侧腹，建立荷瘤小鼠模型，以进一步验证研究结果。
结果
SJZD中共有117种化合物。SJZD和GC分别有161个和3288个潜在靶点，其中123个靶点重叠。网络分析表明，槲皮素、山奈酚、芒柄花素、人参皂苷、白术内酯III等是生物活性分子。肿瘤坏死因子（TNF）、白细胞介素-6（IL-6）、细胞肿瘤抗原p53（TP53）、转录因子AP-1（JUN）和血管内皮生长因子A（VEGFA）是潜在靶点。KEGG通路富集分析显示，有110条通路参与癌症通路，包括PI3K-AKT信号通路。验证实验表明SJZD抑制肿瘤生长并诱导肿瘤细胞凋亡。此外，SJZD下调VEGFA、诱导型一氧化氮合酶（iNOS）、环氧化酶-2（COX-2）和Bax/Bcl2的表达，并抑制p-PI3K和p-AKT的表达。
结论
SJZD通过调节PI3K/AKT通路抑制血管增生和诱导细胞凋亡来治疗GC。
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