Transcriptomic-Driven Drug Repurposing Reveals SP600125 as a Promising Drug Candidate for the Treatment of Glial-Mesenchymal Transition in Glioblastoma
Abstract
1. Introduction
2. Results
2.1. Exploring Glial-Mesenchymal Transition in TCGA-GBM Dataset
2.2. Identification of Hub Genes in the GMT Regulatory Network
2.3. Assessment of Clinical Relevance for GMT-Associated Hub Genes
2.4. Drug Repurposing via Connectivity Mapping
2.5. Effects of SP600125 on GMT Induced by TGF-β and Hypoxia
3. Discussion
- Vemurafenib: This BRAF inhibitor suppresses EMT in colorectal cancer [67] and melanoma [68] cells and demonstrates prolonged disease control in clinical trials for high-grade glioma [111]. However, since resistance to vemurafenib in melanoma led to a re-emergence of the mesenchymal phenotype [69], future evaluation of its anti-GMT potential should consider the chemoresistant status of GBM cells.
- FG-7142: Although there are no reports on the direct effect of this GABAA receptor agonist on GBM cells, its anti-GMT potency warrants investigation. Activation of the GABAA receptor suppresses brain cancer [115]. Furthermore, moxidectin, an analog of FG-7142, significantly inhibited cancer stem cell properties of medulloblastoma cells [116], which are closely associated with the mesenchymal phenotype of CNS tumors [117].
- Phensuximide: This anticonvulsant has not been previously investigated as an antitumor agent. However, network pharmacology and drug repurposing studies have identified it as a potential therapeutic agent for adrenal cortical [118] and breast [119] carcinomas, including a highly invasive form of the latter [120].
4. Materials and Methods
4.1. Bioinformatics
4.1.1. Data Acquisition
4.1.2. Gene Set Enrichment Analysis
4.1.3. Text Mining Analysis
4.1.4. Survival Analysis
4.1.5. Immune Cell Quantification
4.1.6. Weighted Gene Co-Expression Network Analysis (WGCNA)
4.1.7. Differential Expression Analysis
4.1.8. Gene Network Analysis
4.1.9. Connectivity Map Analysis
4.1.10. Chemoinformatics
4.2. Chemicals and Reagents
4.3. Cell Lines
4.4. Biological Evaluations
4.4.1. Cell Viability Analysis
4.4.2. Wound Healing Assay
4.4.3. Assessment of Cell Morphology
4.4.4. Transwell Migration Assay
4.4.5. Vasculogenic Mimicry Analysis
4.4.6. Western Blot
4.4.7. RT-qPCR
4.4.8. Immunofluorescence
4.4.9. Enzyme-Linked Immunosorbent Assay (ELISA)
4.5. Data Analysis and Visualization
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
BBB | Blood–brain barrier |
CGGA | Chinese Glioma Genome Atlas |
EMT | Epithelial–mesenchymal transition |
GBM | Glioblastoma multiforme |
GMT | Glial-mesenchymal transition |
GSEA | Gene set enrichment analysis |
GSVA | Gene set variation analysis |
NCI | Normalized cell index |
P-gp | P-glycoprotein |
STITCH | Search Tool for Interactions of Chemicals |
STRING | Search Tool for the Retrieval of Interacting Genes/Genomes |
TCGA | The Cancer Genome Atlas |
WGCNA | Weighted correlation network analysis |
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Odarenko, K.V.; Zenkova, M.A.; Markov, A.V. Transcriptomic-Driven Drug Repurposing Reveals SP600125 as a Promising Drug Candidate for the Treatment of Glial-Mesenchymal Transition in Glioblastoma. Int. J. Mol. Sci. 2025, 26, 9772. https://doi.org/10.3390/ijms26199772
Odarenko KV, Zenkova MA, Markov AV. Transcriptomic-Driven Drug Repurposing Reveals SP600125 as a Promising Drug Candidate for the Treatment of Glial-Mesenchymal Transition in Glioblastoma. International Journal of Molecular Sciences. 2025; 26(19):9772. https://doi.org/10.3390/ijms26199772
Chicago/Turabian StyleOdarenko, Kirill V., Marina A. Zenkova, and Andrey V. Markov. 2025. "Transcriptomic-Driven Drug Repurposing Reveals SP600125 as a Promising Drug Candidate for the Treatment of Glial-Mesenchymal Transition in Glioblastoma" International Journal of Molecular Sciences 26, no. 19: 9772. https://doi.org/10.3390/ijms26199772
APA StyleOdarenko, K. V., Zenkova, M. A., & Markov, A. V. (2025). Transcriptomic-Driven Drug Repurposing Reveals SP600125 as a Promising Drug Candidate for the Treatment of Glial-Mesenchymal Transition in Glioblastoma. International Journal of Molecular Sciences, 26(19), 9772. https://doi.org/10.3390/ijms26199772