Network pharmacology alliance with experimental validation unveils the anti-colorectal cancer mechanism of Xianlian Jiedu Decoction

Ethnopharmacological relevance: The Xianlian Jiedu Decoction (XLJDD), a traditional Chinese medicine (TCM) decoction, which is effective in clinical treatment of colorectal cancer (CRC). Nevertheless, the pharmacodynamic material basis and mechanism of its action have not been explored yet.

Aims of the study: To investigate the potential functional components and possible mechanism of XLJDD in anti-CRC.

Materials and methods: The UPLC-Q-TOF-MS method was applied to the qualification of absorbed phytochemical compounds in the plasma of rats administrated with XLJDD. Network pharmacology approach was used to create the compound-target network, GO and KEGG enrichment resolution was used to predict the potential biological mechanism of XLJDD anti-CRC. The binding of potential active ingredients to their targets was demonstrated using AutoDock Tools. And the anti-CRC efficacy of XLJDD was investigated through in vitro and in vivo experiments. Furthermore, the mechanism of XLJDD anti-CRC was validated by western blot.

Results: 14 compounds from XLJDD were detected in the plasma of rats administrated with XLJDD. The results of network pharmacology analysis shown that PI3K/AKT and chemokine signaling pathways were strongly linked to XLJDD against CRC. The potential active compounds berberine, 7-methoxycoumarin and 13-methylberberubine may target PRKACA, PIK3CB, and EGFR to regulate PI3K/AKT signaling pathway, which plays a crucial role in cancer cell proliferation. In vitro experimental results revealed that XLJDD apparently inhibits the cell viability and proliferation of HCT116 cells. In vivo experimental results found that in contrast to the model group, the XLJDD treatment obviously cut down the size and weight of tumor. Further, Western blot results demonstrated that XLJDD significantly inhibited the CXCR2/PI3K/AKT signaling axis.

Conclusion: The therapeutic mechanism of XLJDD against CRC involves inhibiting CRC cells proliferation via modulating the CXCR2/ PI3K/AKT signaling pathway.