In Vitro Validation of Network Pharmacology Predictions: Ginsenoside Rg3 Inhibits Hepatocellular Carcinoma Cell Proliferation via SIRT2
Open Access
- 29 April 2021
- journal article
- research article
- Published by SAGE Publications in Natural Product Communications
- Vol. 16 (4)
- https://doi.org/10.1177/1934578x211004826
Abstract
To elucidate the molecular mechanisms underlying the therapeutic activity of ginsenoside Rg3 (Gs-Rg3) in the context of hepatocellular carcinoma (HCC). Methods Relevant databases were searched to identify protein targets that were both dysregulated and implicated in HCC, as well as targeted by Gs-Rg3. Generation of a protein-protein interaction network facilitated the selection of connected nodes for the construction of a shared disease- and drug-target interaction network model, and topological analysis identified the most highly connected nodes. Targets were annotated with their associated Gene Ontology terms, followed by Kyoto Encyclopedia of Genes and Genomes biological pathway enrichment analysis. In vitro experiments using 2 hours CC cell lines (Bel-7402 and HCCLM3) were performed to investigate the impact of Gs-Rg3 on cell proliferation, viability, cell cycle, cyclin D1 and sirtuin 2 (SIRT2) levels, and global cellular histone acetylation (specifically H3K18ac and H4K16ac). Results Network pharmacology suggested that Gs-Rg3 synergistically targets multiple proteins and pathways relevant to HCC pathogenesis, including those involved in cell cycle and proliferation. In vitro experiments confirmed that Gs-Rg3 dose-dependently inhibits cell proliferation and viability; induces G1 phase cell cycle arrest; decreases cyclin D1, cyclin-dependent kinase 2 (CDK2), and SIRT2 levels; and enhances global H3K18ac and H4K16ac. Conclusions Hypotheses derived from the network analysis were confirmed in vitro. Gs-Rg3 induces G1 phase cell cycle arrest, concomitant with decreased cyclin D1 and CDK2 levels, suggesting a possible mechanism for inhibiting proliferation. In addition, Gs-Rg3 decreases SIRT2 levels, concomitant with enhanced global H3K18ac and H4K16ac. These findings provide a theoretical basis and a support for further preclinical study of the safety and antineoplastic molecular mechanisms of Gs-Rg3, with the goal of eventual clinical translation.Keywords
Funding Information
- National Natural Science Foundation of China (81903876)
- Department of Science and Technology of Jilin Province (20170309005YY,20200504005YY)
This publication has 31 references indexed in Scilit:
- Ginsenoside Rg3 inhibits colon cancer cell migration by suppressing nuclear factor kappa B activityJournal of Traditional Chinese Medicine, 2015
- Liver cancer: Approaching a personalized careJournal of Hepatology, 2015
- Chemical constituents and bioactivities of Panax ginseng (C. A. Mey.)Drug Discoveries & Therapeutics, 2015
- Ginsenoside 20(S)-Rg3 Targets HIF-1α to Block Hypoxia-Induced Epithelial-Mesenchymal Transition in Ovarian Cancer CellsPLOS ONE, 2014
- Synergistic antitumor effect of ginsenoside Rg3 and cisplatin in cisplatin-resistant bladder tumor cell lineOncology Reports, 2014
- Anti-hepatoma cells function of luteolin through inducing apoptosis and cell cycle arrestTumor Biology, 2013
- Hepatocellular carcinomaThe Lancet, 2012
- Antitumor effects of ginsenoside Rg3 on human hepatocellular carcinoma cellsMolecular Medicine Reports, 2012
- Ginsenoside Rg3 inhibit hepatocellular carcinoma growthviaintrinsic apoptotic pathwayWorld Journal of Gastroenterology, 2011
- Systematic review of hepatocellular adenoma in China and other regionsJournal of Gastroenterology and Hepatology, 2010