Integrating Network Pharmacology and Experimental Verification to Explore the Mechanism of Effect of Zuojin Pills in Pancreatic Cancer Treatment

Abstract

Background and Aim

Pancreatic cancer is one of the most malignant tumors worldwide. Zuojin pills (ZJP), a traditional Chinese medicine (TCM) formula, which can treat a variety of cancers. However, the active compounds present in ZJP and the potential mechanisms through which ZJP acts against pancreatic cancer have not been thoroughly investigated.

Methods

Data on pancreatic cancer-related genes, bioactive compounds, and potential targets of ZJP were downloaded from public databases. Bioinformatics analysis, including protein–protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, was conducted to identify important components, potential targets, and signaling pathways through which ZJP affects pancreatic cancer. The results of this analysis were verified by in vitro experiments.

Results

The network pharmacology analysis results showed that 41 compounds and 130 putative target genes of ZJP were associated with anti-pancreatic cancer effects. ZJP may exert its inhibitory effects against pancreatic cancer by acting on key targets such as JUN, TP53, and MAPK1. Moreover, KEGG analysis indicated that the anti-pancreatic cancer effect of ZJP was mediated by multiple pathways, such as the PI3K-AKT, IL-17, TNF, HIF-1, and P53 signaling pathways. Among these, the PI3K-AKT signaling pathway, which included the highest number of enriched genes, may play a more important role in treating pancreatic cancer. The in vitro results showed that ZJP significantly inhibits the cell cycle and cell proliferation through the PI3K/AKT/caspase pathway and that it can induce apoptosis of pancreatic cancer cells, consistent with the results predicted by network pharmacological methods.

Conclusion

This study preliminarily investigated the pharmacological effects of ZJP, which appear to be mediated by multiple compounds, targets and pathways, and its potential therapeutic effect on pancreatic cancer. Importantly, our work provides a promising approach for the identification of compounds in TCM and the characterization of therapeutic mechanisms.

Keywords:

• pancreatic cancer
• Zuojin pill
• network pharmacology
• traditional Chinese medicine
• proliferation
• apoptosis

Acknowledgments

This study was supported by the Zhejiang Province Public Welfare Technology Application Research Project (LGF21H160022); Zhejiang Medical and Health Science and Technology Program (2017KY711); and Project of Taizhou Central Hospital (2019KT003).

Abbreviations

AKT, serine-threonine kinase; BAD, BCL2 associated agonist of cell death; BPs, biological processes; CCND1, cyclin D1; C-D-T, Herb-disease-target; C-P-T, compound-pathway-target; CCs, Cell components; DL, drug-likeness; DMSO, dimethyl sulfoxide; EF, evodiae fructus; EGFR, epidermal growth factor receptor; GO, gene ontology; HIF-1, hypoxia-inducible factor 1; HCC, Hepatocellular carcinoma; IL-17, Interleukin 17; IC₅₀, 50% inhibitory concentration; JUN, jun proto-oncogene; KEGG, Kyoto Encyclopedia of Genes and Genomes; MFs, molecular functions; MAPK1, Mitogen-activated protein kinase 1; NF-κB, Nuclear factor kappa B; OB, oral bioavailability; OMIM, Online Mendelian Inheritance in Man; PPI, Protein–protein interaction; PI3K, Phosphatidylinositol 3-kinase; RC, Rhizoma Coptidis; TCM, Traditional Chinese medicine; TCMSP, Traditional Chinese Medicines for Systems Pharmacology; TNF, tumor necrosis factor; TP53, tumor protein p53; ZJP, Zuojin pills.

Disclosure

The authors report no conflicts of interest in this work.