Abstract
In China, a traditional Chinese medicine formulation called astragalus membranaceus (AM) has been utilised for more than 20 years to treat tumors with extraordinary effectiveness. The fundamental mechanisms, nevertheless, are still not well understood. The aim of this study is identifying its possible therapeutic targets and to evaluate the effects of AM in combination with a PARP inhibitor (olaparib) in the treatment of BRCA wild-type ovarian cancer. Significant genes were collected from Therapeutic Target Database and Database of Gene-Disease Associations. The components of AM were analyzed using the Traditional Chinese Medicine System Pharmacology (TCMSP) database to screen the active ingredients of AM based on their oral bioavailability and drug similarity index. In order to find intersection targets, Venn diagrams and STRING website diagrams were employed. STRING was also used to create a protein-protein interaction network. In order to create the ingredient-target network, Cytoscape 3.8.0 was used. DAVID database was utilized to carry out enrichment and pathway analyses. The binding ability of the active compounds of AM to the core targets of AM-OC was verified with molecular docking using AutoDock software. Experimental validations, including cell scratch, cell transwell, cloning experiment, were conducted to verify the effects of AM on OC cells. A total of 14 active ingredients of AM and 28 AM-OC-related targets were screened by network pharmacology analysis. The ten most significant Gene Ontology (GO) biological function analyses, as well as the 20 foremost Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways were selected. Moreover, molecular docking results showed that bioactive compound (quercetin) demonstrated a good binding ability with tumor protein p53 (TP53), MYC, vascular endothelial growth factor A (VEGFA), phosphatase and tensin homolog (PTEN), AKT serine/threonine kinase 1 (AKT1) and cyclin D1 (CCND1) oncogenes. According to experimental methods, in vitro OC cell proliferation and migration appeared to be inhibited by quercetin, which also increased apoptosis. In addition, the combination with olaparib further enhanced the effect of quercetin on OC. Based on network pharmacology, molecular docking, and experimental validation, the combination of PARP inhibitor and quercetin enhanced the anti-proliferative activity in BRCA wild-type ovarian cancer cells, which supplies the theoretical groundwork for additional pharmacological investigation.
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