Modulating Wnt/β-Catenin Signaling Pathway on U251 and T98G Glioblastoma Cell Lines Using a Combination of Paclitaxel and Temozolomide, A Molecular Docking Simulations and Gene Expression Study
One of the most lethal cancers, glioblastoma (GBM), affects 14.5% of all central nervous system (CNS) tumors. Patients diagnosed with GBM have a meager median overall survival (OS) of 15 months. Extensive genetic analysis has shown that many dysregulated pathways, including the Wnt/β-catenin signali...
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Veröffentlicht in: | Chemical & pharmaceutical bulletin 2023/10/01, Vol.71(10), pp.766-774 |
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Sprache: | eng |
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Zusammenfassung: | One of the most lethal cancers, glioblastoma (GBM), affects 14.5% of all central nervous system (CNS) tumors. Patients diagnosed with GBM have a meager median overall survival (OS) of 15 months. Extensive genetic analysis has shown that many dysregulated pathways, including the Wnt/β-catenin signaling system, contribute to the pathogenicity of GBM. Paclitaxel (PTX) and temozolomide (TMZ) are recognized to have therapeutic potential in several types of cancer, including GBM. This work aimed to examine the impact of PTX and TMZ on the human glioma cell lines U251 and T98G using molecular docking simulations and gene expression profiles in the Wnt/β-catenin signaling pathway. Standard procedure for Molecular Docking simulation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay, and Flow Cytometry assay was used. Genes implicated in the Wnt/β-catenin signaling pathway, including Dvl, Axin, APC, β-catenin, and glycogen synthase kinase3-β (GSK3β), were subjected to real-time PCR. The estimated parameters for targets revealed that the average binding energy and inhibition constant (Ki) for the DVL, β-Catenin, and GSK3β, when targeted by PTX, were − 5.01 kcal/mol, − 5.4 kcal/mol, and − 9.06 kcal/mol, respectively. This energy range was − 6.34 kcal/mol for DVL, − 5.52 kcal/mol for β-Catenin, and − 5.66 kcal/mol for GSK3β as a result of TMZ’s inhibitory actions. Gene expression analyses indicated that PTX and PTX/TMZ suppressed GSK3β (p |
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ISSN: | 0009-2363 1347-5223 |
DOI: | 10.1248/cpb.c22-00815 |