1. Potential of semen coicis in enhancing the anti-tumor effects of PD-1 inhibitor on A549 cell lines by blocking the PI3K-AKT-mTOR pathway.
- Author
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Fu ZY, Huang Y, Lian LS, Huang HT, Zhan SF, Cai Y, Li JX, and Liu XH
- Subjects
- Humans, A549 Cells, B7-H1 Antigen metabolism, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Drug Synergism, Immune Checkpoint Inhibitors pharmacology, Molecular Docking Simulation, Phosphatidylinositol 3-Kinases metabolism, Protein Interaction Maps drug effects, Proto-Oncogene Proteins c-akt metabolism, TOR Serine-Threonine Kinases metabolism, TOR Serine-Threonine Kinases antagonists & inhibitors, Lung Neoplasms drug therapy, Lung Neoplasms metabolism, Lung Neoplasms pathology, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Signal Transduction drug effects, Coix chemistry, Antineoplastic Agents pharmacology
- Abstract
Background: The objective of this research was to investigate how the combination of semen coicis extract and PD-1 inhibitors can potentially work together to enhance the anti-tumor effects, with a focus on understanding the underlying mechanism., Methods: We obtained the active components and specific targets of semen coicis in the treatment of NSCLC from various databases, namely TCMSP, GeneCard, and OMIM. By utilizing the STRING database and Cytoscape software, we established a protein interaction network (PPI) for the active ingredient of semen coicis and the target genes related to NSCLC. To explore the potential pathways involved, we conducted gene ontology (GO) and biological pathway (KEGG) enrichment analyses, which were further supported by molecular docking technology. Additionally, we conducted cyto-inhibition experiments to verify the inhibitory effects of semen coicis alone or in combination with a PD-1 inhibitor on A549 cells, along with examining the associated pathways. Furthermore, we investigated the synergistic mechanism of these two drugs through cytokine release experiments and the PD-L1 expression study on A549 cells., Results: Semen coicis contains two main active components, Omaine and (S)-4-Nonanolide. Its primary targets include PIK3R1, PIK3CD, PIK3CA, AKT2, and mTOR. Molecular docking experiments confirmed that these ingredients and targets form stable bonds. In vitro experiments showed that semen coicis demonstrates inhibitory effects against A549 cells, and this effect was further enhanced when combined with PD-1 inhibitors. PCR and WB analysis confirmed that the inhibition of the PI3K-AKT-mTOR pathway may contribute to this effect. Additionally, semen coicis was observed to decrease the levels of IFN-γ, IL-6, and TNF-α, promoting the recovery of the human anti-tumor immune response. And semen coicis could inhibit the induced expression of PD‑L1 of A549 cells stimulated by IFN‑γ as well., Conclusion: Semen coicis not only has the ability to kill tumor cells directly but also alleviates the immunosuppression found in the tumor microenvironment. Additionally, it collaboratively enhances the effectiveness of PD-1 inhibitors against tumors by blocking the activation of PI3K-AKT-mTOR., (© 2024. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)
- Published
- 2024
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