Network pharmacology, molecular docking and experimental verification help unravel chelerythrine's potential mechanism in the treatment of gastric cancer

Abstract

Gastric cancer (GC) is a deadly malignant tumor with a high fatality rate and limited curative options. A growing body of research suggests that network pharmacology can replace traditional methods for determining the precise mechanism of action of medicinal substances in conditions such as cancer. The goal of this study was to clarify the biological mechanism of chelerythrine (CHE) and develop a prediction target for CHE against GC using network pharmacology. First, the genes related to GC were identified from the databases Genecards, Disgenet, Online Mendelian Inheritance in Man, Therapeutic Target Database, and Drugbank, and the targets of CHE were obtained from the SwissTargetPrediction database. Fifty linked targets were identified as anti-GC targets of CHE. Functional enrichment and pathway analyses revealed important biological mechanisms mediated by these targets. The core target PIK3CA of CHE anti-GC was obtained using the protein–protein interaction network, CytoHubba plug-in, and Human Protein Atlas. Molecular docking studies revealed that CHE has a strong affinity for PIK3CA (−10.5 kcal/mol). In addition, we used MTT, colony formation, wound-healing, Transwell®, and flow cytometry experiments to confirm that CHE inhibited the proliferation and migration of GC cells and induced cell cycle arrest and apoptosis. Finally, western blotting results showed that CHE downregulated the expression of the PIK3CA protein and inhibited the activation of the PI3K/AKT signaling pathway. Therefore, we concluded that CHE inhibited GC cell proliferation and migration and induced cell cycle arrest and apoptosis by targeting the PIK3CA protein to inhibit the PI3K/AKT pathway activity.