Network Pharmacology, Molecular Docking, and in vitro Experiments Reveal the Role and Mechanism of Tanshinone IIA in Colorectal Cancer Treatment Through the PI3K/AKT Pathway.

PURPOSE: To examine the roles and mechanisms of tanshinone IIA (Tan-IIA) in colorectal cancer (CRC) using network pharmacology, molecular docking, and in vitro experiments.

METHODS

In network pharmacology studies, Tan-IIA targets for treating CRC were identified using public databases. Employing the protein-protein interaction (PPI) network, gene ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the core genes and mechanisms of action of Tan-IIA were obtained. Core targets were validated using Gene Expression Profiling Interactive Analysis, the Human Protein Atlas, DriverDBv3, cBioPortal, and the Tumor Immune Estimation Resource database. Molecular docking validates the binding affinity of Tan-IIA to some key targets. Network pharmacology and molecular docking results were validated via in vitro experiments.

RESULTS

Intersecting Tan-IIA and CRC targets led to the identification of 25 potential targets. PPI analysis identified 10 core targets of Tan-IIA for CRC treatment. Database validation revealed that these core targets were expressed at varying levels in both normal and cancer tissues. Their expression could influence patient prognosis and immune cell infiltration levels. GO analysis revealed 170 biological processes, 42 cellular components, and 83 molecular functions. KEGG analysis indicated that Tan-IIA affected CRC through multiple pathways, including the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), cAMP, and TNF signaling pathways, with the PI3K/AKT pathway being the most enriched. Molecular docking results indicated that Tan-IIA effectively binds to PI3K, AKT, and other partial core targets. In vitro experiments revealed that Tan-IIA suppressed the multiplication and migration of HCT116 and SW480 cells, induced apoptosis, and reduced the PI3K/AKT pathway indicator protein expression, which was reversed by the PI3K/AKT pathway agonist insulin-like growth factor-1.

CONCLUSION

Network pharmacology, molecular docking, and in vitro validation confirmed that Tan-IIA contributes to CRC treatment through the PI3K/AKT pathway, providing theoretical and experimental foundations for its potential clinical application.