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Network Pharmacology and in vitro Experimental Verification on Intervention of Oridonin on Non-Small Cell Lung Cancer
Ke Chang1,2, Li-Fei Zhu1, Ting-Ting Wu1
1Department of Pharmacy, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China.
Objective:
To explore the key target molecules and potential mechanisms of oridonin against non-small cell lung cancer (NSCLC).
Methods:
The target molecules of oridonin were retrieved from SEA, STITCH, SuperPred and TargetPred databases; target genes associated with the treatment of NSCLC were retrieved from GeneCards, DisGeNET and TTD databases. Then, the overlapping target molecules between the drug and the disease were identified. The protein-protein interaction (PPI) was constructed using the STRING database according to overlapping targets, and Cytoscape was used to screen for key targets. Molecular docking verification were performed using AutoDockTools and PyMOL software. Using the DAVID database, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted. The impact of oridonin on the proliferation and apoptosis of NSCLC cells was assessed using cell counting kit-8, cell proliferation EdU image kit, and Annexin V-FITC/PI apoptosis kit respectively. Moreover, real-time quantitative PCR and Western blot were used to verify the potential mechanisms.
Results:
Fifty-six target molecules and 12 key target molecules of oridonin involved in NSCLC treatment were identified, including tumor protein 53 (TP53), Caspase-3, signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein kinase kinase 8 (MAPK8), and mammalian target of rapamycin (mTOR). Molecular docking showed that oridonin and its key target molecules bind spontaneously. GO and KEGG enrichment analyses revealed cancer, apoptosis, phosphoinositide-3 kinase/protein kinase B (PI3K/Akt), and other signaling pathways. In vitro experiments showed that oridonin inhibited the proliferation, induced apoptosis, downregulated the expression of Bcl-2 and Akt, and upregulated the expression of Caspase-3.
Conclusion:
Oridonin can act on multiple targets and pathways to exert its inhibitory effects on NSCLC, and its mechanism may be related to upregulating the expression of Caspase-3 and downregulating the expressions of Akt and Bcl-2.
Insights
Oridonin shows potential against non-small cell lung cancer (NSCLC) by targeting multiple molecules and pathways. It inhibits cancer cell proliferation and promotes apoptosis, offering a promising therapeutic avenue for NSCLC treatment.
Area of Science:
- Pharmacology
- Oncology
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide.
- Identifying novel therapeutic agents and their mechanisms of action is crucial for improving patient outcomes.
Purpose of the Study:
- To elucidate the key molecular targets of oridonin in non-small cell lung cancer (NSCLC).
- To investigate the underlying mechanisms by which oridonin exerts its anti-cancer effects in NSCLC.
Main Methods:
- Computational analysis using databases (SEA, STITCH, SuperPred, TargetPred, GeneCards, DisGeNET, TTD, STRING) to identify drug-target interactions and construct protein-protein networks.
- Molecular docking, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed.
- In vitro assays (CCK-8, EdU, Annexin V-FITC/PI) and molecular biology techniques (RT-qPCR, Western blot) were used to assess oridonin's effects on NSCLC cell proliferation, apoptosis, and key protein expression.
Main Results:
- Fifty-six potential target molecules for oridonin were identified, with 12 key targets including TP53, Caspase-3, STAT3, MAPK8, and mTOR.
- Molecular docking confirmed spontaneous binding of oridonin to its key targets.
- Oridonin significantly inhibited NSCLC cell proliferation, induced apoptosis, downregulated Bcl-2 and Akt expression, and upregulated Caspase-3 expression, implicating pathways like PI3K/Akt.
Conclusions:
- Oridonin demonstrates multi-target and multi-pathway inhibitory effects against NSCLC.
- The anti-cancer mechanism of oridonin in NSCLC involves the upregulation of Caspase-3 and downregulation of Akt and Bcl-2.
