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Published on: September 12, 2019
Target prediction and potential application of dihydroartemisinin on hepatocarcinoma treatment
Wenjia Guo1, Yu'e Liu2, Bingdi Chen3
1Department of Laboratory Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Abstract:
With high incidence of hepatocarcinoma and limited effective treatments, most patients suffer in pain. Antitumor drugs are single-targeted, toxicity, causing adverse side effects and resistance. Dihydroartemisinin (DHA) inhibits tumor through multiple mechanisms effectively. This study explores and evaluates safety and potential mechanism of DHA towards human hepatocarcinoma based on network pharmacology in a comprehensive way. Adsorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of DHA were evaluated with pkCSM, SwissADME, and ADMETlab. Potential targets of DHA were obtained from SwissTargetPrediction, Drugbank, TargetNET, and PharmMapper. Target gene of hepatocarcinoma was obtained from OMIM, GeneCards, and DisGeNET. Overlapping targets and hub genes were identified and analyzed for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway. Molecular docking was utilized to investigate the interactions sites and hydrogen bonds. Cell counting kit-8 (CCK8), wound healing, invasion, and migration assays on HepG2 and SNU387 cell proved DHA inhibits malignant biological features of hepatocarcinoma cell. DHA is safe and desirable for clinical application. A total of 131 overlapping targets were identified. Biofunction analysis showed targets were involved in kinase activity, protein phosphorylation, intracellular reception, signal transduction, transcriptome dysregulation, PPAR pathway, and JAK-STAT signaling axis. Top 9 hub genes were obtained using MCC (Maximal Clique Centrality) algorithm, namely CDK1, CCNA2, CCNB1, CCNB2, KIF11, CHEK1, TYMS, AURKA, and TOP2A. Molecular docking suggests that all hub genes form a stable interaction with DHA for optimal binding energy were all less than - 5 kcal/mol. Dihydroartemisinin might be a potent and safe anticarcinogen based on its biological safety and effective therapeutic effect.
Insights
Dihydroartemisinin (DHA) shows potential as a safe and effective treatment for hepatocarcinoma. Network pharmacology and cell assays confirm DHA
Area of Science:
- Pharmacology and Toxicology
- Computational Biology
- Oncology
Background:
- Hepatocarcinoma presents a significant clinical challenge due to high incidence and limited effective therapies.
- Existing antitumor drugs often exhibit single-target specificity, leading to toxicity, adverse effects, and drug resistance.
- Dihydroartemisinin (DHA) demonstrates multi-mechanism antitumor properties, suggesting therapeutic potential.
Purpose of the Study:
- To comprehensively explore and evaluate the safety and potential mechanisms of Dihydroartemisinin (DHA) against human hepatocarcinoma.
- To utilize network pharmacology to identify key targets and pathways involved in DHA's anti-hepatocarcinoma activity.
- To validate the therapeutic efficacy and safety profile of DHA for clinical consideration.
Main Methods:
- Evaluated Adsorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties using pkCSM, SwissADME, and ADMETlab.
- Identified potential DHA targets and hepatocarcinoma-related genes from multiple databases (SwissTargetPrediction, Drugbank, OMIM, GeneCards, etc.).
- Performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome pathway analyses on overlapping targets and hub genes.
- Utilized molecular docking to assess binding interactions between DHA and identified hub genes.
- Conducted in vitro assays (CCK8, wound healing, invasion, migration) on HepG2 and SNU387 hepatocarcinoma cell lines.
Main Results:
- Identified 131 overlapping targets between DHA and hepatocarcinoma, with key pathways including kinase activity, protein phosphorylation, and JAK-STAT signaling.
- Determined nine hub genes (CDK1, CCNA2, CCNB1, CCNB2, KIF11, CHEK1, TYMS, AURKA, TOP2A) crucial for DHA's mechanism of action.
- Molecular docking confirmed stable interactions between DHA and hub genes, with binding energies below -5 kcal/mol.
- In vitro assays demonstrated that DHA effectively inhibits malignant biological features of hepatocarcinoma cells.
Conclusions:
- Dihydroartemisinin (DHA) exhibits favorable ADMET properties and is deemed safe for clinical application.
- DHA demonstrates significant potential as a multi-targeted therapeutic agent for hepatocarcinoma.
- The study provides a strong foundation for DHA's development as a potent and safe anticarcinogen.
