Combining HDAC and MEK Inhibitors with Radiation against Glioblastoma-Derived Spheres.

Eno I Essien,Thomas P Hofer,Nataša Anastasov,Michael J Atkinson

doi:10.3390/cells11050775

Eno I Essien, Thomas P Hofer + Show 2 more

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https://doi.org/10.3390/cells11050775

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Journal: Cells	Publication Date: Feb 23, 2022
Citations: 12	License type: CC BY 4.0

Affiliation: Helmholtz Zentrum München, Technical University of Munich

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.

Highlights

Glioblastoma (GB), a grade IV astrocytoma, is one of the most aggressive primary brain tumors
These results suggest that combining HDAC and MAPK/ERK kinase (MEK) inhibition with radiation may offer a new strategy to improve the treatment of glioblastoma
Since sphere formation measures the self-renewal of stem-like cells [35–37], these results suggest that the combined treatment of the histone deacetylase inhibitor (HDACi) and MAPK/ERK kinase inhibitor (MEKi) with radiation could potentially decrease the self-renewal ability of glioblastoma stem-like cells (GSLCs)

Summary

Introduction

Glioblastoma (GB), a grade IV astrocytoma, is one of the most aggressive primary brain tumors. Despite the adoption of a standard therapy combining surgical resection, radiotherapy and chemotherapy with temozolomide (TMZ), the poor prognoses of patients with GB have failed to improve, with a median survival of only. One factor that limits the success of GB therapy is the presence of a sub-population of glioblastoma stem-like cells (GSLCs) within the tumor [2]. GSLCs possess characteristics of tissue stem cells, including the ability to self-renew and to generate further malignant progeny [3]. GSLCs are considered to be drug and radiation resistant, as well as promote tumor angiogenesis and tumor recurrence, all of which hinder the effective treatment of GB [2,4,5]. A therapeutic strategy that improves the control of GSLCs offers an opportunity to improve treatment outcomes for GB

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