AUTHOR=Li Jinxiao , Zhou Fangyuan , Shang Luorui , Liu Na , Liu Yuhan , Zhang Mengqi , Wang Shuhan , Yang Shenglan TITLE=Integrated network pharmacology and experimental verification to investigate the mechanisms of YYFZBJS against colorectal cancer via CDK1/PI3K/Akt signaling JOURNAL=Frontiers in Oncology VOLUME=12 YEAR=2022 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2022.961653 DOI=10.3389/fonc.2022.961653 ISSN=2234-943X ABSTRACT=Background

Colorectal cancer (CRC) is a common digestive tract malignancy with rising incidence and morbidity worldwide during recent years. Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS), a traditional Chinese medicine formula, has showed positive effects against cancers. However, the mechanisms underlying its anticancer effects requires investigation.

Methods

Information on bioactive compounds, potential YYFZBJS targets, and CRC-associated genes, was obtained from public databases. The key targets and ingredients as well their corresponding signaling pathways were identified using bioinformatic approaches, including Kyoto encyclopedia of genes and genomes (KEGG) analyses, gene ontology (GO), and protein–protein interaction (PPI). Subsequently, molecular docking was used to verify the main compounds-targets. Potential YYFZBJS therapeutic effects against CRC were validated in vitro and in vivo.

Results

Using pharmacological network analysis, 40 YYFZBJS active compounds and 21 potential anti-CRC targets were identified. YYFZBJS was an important regulator of CRC through various targets and signaling pathways, particularly the cell cycle and PI3K/AKT pathway. Additionally, YYFZBJS suppressed the proliferation of CRC cells. Flow cytometry showed that YYFZBJS induced apoptosis and cell cycle arrest in the G2/M phase. Western blotting analysis indicated that YYFZBJS reduced the protein levels of CDK1, p-AKT, and p-PI3K, without altering total PI3K and AKT protein levels. In vivo analysis found that YYFZBJS inhibited tumor growth and PI3K/AKT signaling in a mouse model of CRC.

Conclusion

As predicted by network pharmacology and validated by the experimental results, YYFZBJS inhibited proliferation, induced apoptosis and arrested cell cycle progression in CRC by modulating the CDK1/PI3K/Akt signaling pathway.