Abstract
Purpose This study was aimed at exploring the regulatory mechanism of Xiaoyao San (XYS) and its main compound, Stigmasterol, in the biological network and signaling pathway of ovarian cancer (OC) through network pharmacology-based analyses and experimental validation. Methods The active compounds and targets of XYS were studied by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The GeneCards and OMIM databases were used to screen common targets of XYS in the treatment of OC. Combined with the STRING database and Cytoscape 3.6.0, the core compounds and targets of XYS were obtained. GO and KEGG pathway enrichment analyses of core target genes were carried out by using the Metascape and DAVID databases. Molecular docking has been achieved by using the AutoDock Vina program to discuss the interaction of the core targets and compounds of XYS in the treatment of OC. The effect of Stigmasterol on proliferation and migration were assessed by CCK8 and wound healing assay. Western blot and qRT-PCR were used to analyze the protein and mRNA expressions of PI3K, Akt, and PTEN after treatment of Stigmasterol. Results A total of 113 common targets of XYS for the treatment of OC were obtained from 975 targets related to OC and 239 targets of XYS's effect. The main compounds of XYS include Quercetin, Naringenin, Isorhamnetin, and Stigmasterol, which mainly regulate the targets such as TP53, Akt1, and MYC and PI3K/Akt, p53, and cell cycle signal pathways. At the same time, molecular docking showed that Stigmasterol and Akt1 had good docking conformation. Stigmasterol inhibited OC cell proliferation and migration in vitro and reduced the protein and mRNA expressions of the PI3K/Akt signaling pathway. Conclusion Stigmasterol as the one of the main compounds of XYS suppresses OC cell activities through the PI3K-Akt signaling pathway.
Highlights
Ovarian cancer (OC) is the most frequently diagnosed and highest mortality in gynecological cancers
A number of clinical trials have shown that the traditional Chinese medicine combination with chemotherapy or radiotherapy may benefit OC patients [3,4,5]
The expression of Akt1 and TP53 was higher and that of MYC was lower in OC tissues than in normal tissues (Figure 1)
Summary
Ovarian cancer (OC) is the most frequently diagnosed and highest mortality in gynecological cancers. The 5-year overall survival rate was about 40% when most patients were late at the time of discovery because the lack of symptoms was not obvious [1, 2]. The main treatment of OC is surgery, platinum-based chemotherapy, and radiotherapy. 30-45% BRCA1/2 mutation patients showed response to the PARP inhibitor Olaparib. Relapse and metastasis were considered to be due to resistance and toxicities. How to increase the response rate and relieve side effects still remains to be completed. A number of clinical trials have shown that the traditional Chinese medicine combination with chemotherapy or radiotherapy may benefit OC patients [3,4,5]
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