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Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres
Eno I Essien1,2, Thomas P Hofer3, Michael J Atkinson4
1Institute of Biological and Medical Imaging, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Abstract:
Glioblastoma stem-like cells (GSLCs) in glioblastoma limit effective treatment and promote therapeutic resistance and tumor recurrence. Using a combined radiation and drug-screening platform, we tested the combination of a histone deacetylase inhibitor (HDACi) and MAPK/ERK kinase inhibitor (MEKi) with radiation to predict the efficacy against GSLCs. To mimic a stem-like phenotype, glioblastoma-derived spheres were used and treated with a combination of HDACi (MS-275) and MEKi (TAK-733 or trametinib) with 4 Gy irradiation. The sphere-forming ability after the combined radiochemotherapy was investigated using a sphere formation assay, while the expression levels of the GSLC markers (CD44, Nestin and SOX2) after treatment were analyzed using Western blotting and flow cytometry. The combined radiochemotherapy treatment inhibited the sphere formation in both glioblastoma-derived spheres, decreased the expression of the GSLC markers in a cell-line dependent manner and increased the dead cell population. Finally, we showed that the combined treatment with radiation was more effective at reducing the GSLC markers compared to the standard treatment of temozolomide and radiation. These results suggest that combining HDAC and MEK inhibition with radiation may offer a new strategy to improve the treatment of glioblastoma.
Insights
Combining HDAC and MEK inhibitors with radiation effectively targets glioblastoma stem-like cells (GSLCs), reducing their markers and sphere formation. This novel approach shows promise against glioblastoma, outperforming standard treatments.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Drug Discovery
Background:
- Glioblastoma stem-like cells (GSLCs) drive therapeutic resistance, recurrence, and limit treatment efficacy.
- Targeting GSLCs is crucial for developing more effective glioblastoma therapies.
Purpose of the Study:
- To evaluate the efficacy of combining histone deacetylase inhibitors (HDACi) and MAPK/ERK kinase inhibitors (MEKi) with radiation against glioblastoma stem-like cells.
- To assess the impact of this combined treatment on GSLC marker expression and sphere-forming capacity.
Main Methods:
- Glioblastoma-derived spheres were treated with MS-275 (HDACi) and trametinib (MEKi) alongside 4 Gy irradiation.
- Sphere formation assays, Western blotting, and flow cytometry were used to analyze treatment effects on GSLC markers (CD44, Nestin, SOX2).
Main Results:
- The combined radiochemotherapy significantly inhibited sphere formation and decreased GSLC marker expression in a cell-line dependent manner.
- This combination therapy increased the population of dead cells.
- Combined HDAC and MEK inhibition with radiation was more effective in reducing GSLC markers than standard temozolomide and radiation therapy.
Conclusions:
- Combining HDAC and MEK inhibition with radiation presents a promising new therapeutic strategy for glioblastoma.
- This approach demonstrates superior efficacy in targeting glioblastoma stem-like cells compared to current standard treatments.
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