Exploring the Molecular Targets and Therapeutic Potential of Coptisine in Colon Cancer: A Network Pharmacology Approach

Introduction: Colon cancer is a frequent malignancy, and surgery is still the primary therapy for people with colon cancer. Other treatments, including radiation, chemotherapy, and biologic therapy, may be utilized as a supplement. Chemotherapy, a prominent treatment for colon cancer, has failed to provide positive outcomes. This necessitates the development of more effective and less harmful treatment drugs. Coptisine was discovered to inhibit the development of colon cancer cell line HCT-116 in vivo, decrease the growth of HCT-116 cells, and cause apoptosis in vitro in colon cancer. Coptisine (COP) has shown antitumor activity in colon cancer, but its molecular mechanism and its molecular targets have not been fully understood. Methods: In this study, the biological behavior was verified in vitro. The targets of Huanglian alkaloids on colon cancer were predicted, and the protein-protein interaction (PPI) network was constructed. The core targets of safranine for colon cancer were extracted and analyzed by GO and KEGG enrichment to identify the possible molecular mechanisms of safranine treatment. Western blot was used to detect the changes of related pathway proteins in colon cancer cells. The differential expression of hub genes in colon cancer was analyzed using the GEPIA2 website. The binding ability of safranine to the target was verified by molecular docking. Finally, the targets were preliminarily verified by q-PCR analysis. Results: Coptisine can inhibit the survival, migration, and proliferation of colon cancer cells DLD1 and HCT-116. Based on network pharmacology, ninety-one targets for colon cancer were screened. ESR1, ALB, AR, CDK2, PARP1, HSP90AB1, IGF1R, CCNE1, and CDC42 were found in the top 10. Enrichment analysis showed that these targets were mainly related to pathways in cancer, FC γ R-mediated phagocytosis, prostate cancer, progesterone-mediated oocyte maturation, the oestrogen signal pathway, proteoglycan in cancer and the PI3K-Akt signal pathway. WB results showed that after the treatment of colon cancer DLD1 cells with coptisine, the expression of P-AKT and AKT decreased, that of its downstream protein Bcl-2 decreased, and that of BAX increased. Differential expression analysis of hub genes showed that CCNE1, CDK2, HSP90AB1, and CHEK2 were upregulated in colon cancer samples, and molecular docking showed that these targets had a good ability to bind to coptisine. After the treatment of colon cancer DLD1 cells with coptisine, q-PCR results showed that CCNE1 and HSP90AB1 were significantly downregulated, while CDK2 and CHEK2 had no significant changes. Conclusion: Coptisine may be a candidate drug for the treatment of colon cancer, and its therapeutic effect may be related to the cancer pathway and PI3K-Akt signalling pathway. CCNE1 and HSP90AB1 may be potential targets of coptisine in the treatment of colon cancer.