Insights into the antineoplastic mechanism of Chelidonium majus via systems pharmacology approach
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The antineoplastic activity of Chelidonium majus has been reported, but its mechanism of action (MoA) is unsuspected. The emerging theory of systems pharmacology may be a useful approach to analyze the complicated MoA of this multi-ingredient traditional Chinese medicine (TCM).
We collected the ingredients and related compound-target interactions of C. majus from several databases. The bSDTNBI (balanced substructure-drug-target network-based inference) method was applied to predict each ingredient’s targets. Pathway enrichment analysis was subsequently conducted to illustrate the potential MoA, and prognostic genes were identified to predict the certain types of cancers that C. majus might be beneficial in treatment. Bioassays and literature survey were used to validate the in silico results.
Systems pharmacology analysis demonstrated that C. majus exerted experimental or putative interactions with 18 cancer-associated pathways, and might specifically act on 13 types of cancers. Chelidonine, sanguinarine, chelerythrine, berberine, and coptisine, which are the predominant components of C. majus, may suppress the cancer genes by regulating cell cycle, inducing cell apoptosis and inhibiting proliferation.
The antineoplastic MoA of C. majus was investigated by systems pharmacology approach. C. majus exhibited promising pharmacological effect against cancer, and may consequently be useful material in further drug development. The alkaloids are the key components in C. majus that exhibit anticancer activity.
Keywordssystems pharmacology mechanism of action traditional Chinese medicine Chelidonium majus
This work was supported by the National Key Research and Development Program of China (No. 2016YFA0502304), the National Natural Science Foundation of China (Nos. 81673356 and U1603122) and the 111 Project (No. B07023).
- 1.Chen, S.L., Song, J.Y., Sun, C., Xu, J., Zhu, Y.J. and Verpoorte, R. (2015) Herbal genomics: examining the biology of traditional medicine. Science/AAAS Custom Publishing Office, 347, S27–S29Google Scholar
- 8.Wu, Z., Cheng, F., Li, J., Li, W., Liu, G. and Tang, Y. (2017) SDTNBI: an integrated network and chemoinformatics tool for systematic prediction of drug–target interactions and drug repositioning. Brief. Bioinform., 18, 333–347Google Scholar
- 17.Southan, C., Sharman, J. L., Benson, H. E., Faccenda, E., Pawson, A. J., Alexander, S. P. H., Buneman, O. P., Davenport, A. P., McGrath, J. C., Peters, J. A., et al. (2016) The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. Nucleic Acids Res., 44, D1054–D1068CrossRefGoogle Scholar
- 27.Uhlen, M., Zhang, C., Lee, S., Sjöstedt, E., Fagerberg, L., Bidkhori, G., Benfeitas, R., Arif, M., Liu, Z., Edfors, F., et al. (2017) A pathology atlas of the human cancer transcriptome. Science, 357, eaan2507Google Scholar
- 28.Sárközi, Á., Janicsák, G., Kursinszki, L. and Kéry, Á. (2006) Alkaloid composition of Chelidonium majus L. studied by different chromatographic techniques. Chromatographia, 63, S81–S86Google Scholar
- 32.Miller, C. and Koeffler, H. P. (1993) P53 mutations in human cancer. Leukemia, 7, S18–S21Google Scholar
- 33.Achbarou, A., Kaiser, S., Tremblay, G., Ste-Marie, L.-G., Brodt, P., Goltzman, D. and Rabbani, S. A. (1994) Urokinase overproduction results in increased skeletal metastasis by prostate cancer cells in vivo. Cancer Res., 54, 2372–2377Google Scholar
- 37.Chang, F., Lee, J. T., Navolanic, P. M., Steelman, L. S., Shelton, J. G., Blalock, W. L., Franklin, R. A. and Mccubrey, J. A. (2003) Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia, 17, 590–603CrossRefGoogle Scholar
- 46.Ahmad, N., Gupta, S., Husain, M. M., Heiskanen, K. M. and Mukhtar, H. (2000) Differential antiproliferative and apoptotic response of sanguinarine for cancer cells versus normal cells. Clin. Cancer Res., 6, 1524–1528Google Scholar
- 47.Adhami, V. M., Aziz, M. H., Reagan-Shaw, S. R., Nihal, M., Mukhtar, H. and Ahmad, N. (2004) Sanguinarine causes cell cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery. Mol. Cancer Ther., 3, 933–940.Google Scholar
- 53.Rao, P. C., Begum, S., Sahai, M. and Sriram, D. S. (2017) Coptisine-induced cell cycle arrest at G2/M phase and reactive oxygen species–dependent mitochondria-mediated apoptosis in non-small-cell lung cancer A549 cells. Tumour Biol., 39Google Scholar
- 54.Nadova, S., Miadokova, E., Alfoldiova, L., Kopaskova, M., Hasplova, K., Hudecova, A., Vaculcikova, D., Gregan, F. and Cipak, L. (2008) Potential antioxidant activity, cytotoxic and apoptosis-inducing effects of Chelidonium majus L. extract on leukemia cells. Neuroendocrinol. Lett., 29, 649–652Google Scholar
- 55.Deljanin, M., Nikolic, M., Baskic, D., Todorovic, D., Djurdjevic, P., Zaric, M., Stankovic, M., Todorovic, M., Avramovic, D. and Popovic, S. (2016) Chelidonium majus crude extract inhibits migration and induces cell cycle arrest and apoptosis in tumor cell lines. J. Ethnopharmacol., 190, 362–371CrossRefGoogle Scholar
- 56.Zhang, L., Chen, Z. H., Chen, H. Y., Wang, X. Q., Zhang, B. and University, S. (2018) Study on antitumor molecular mechanism of Chelidonium majus based on network pharmacology. Chin. Tradit. Herbal Drugs, 49, 646–657Google Scholar
- 59.Small-Molecule Drug Discovery Suite 2015–2, Schrödinger, LLC, New York, 2015Google Scholar