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

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 5; p. 775
• Main Authors: Essien, Eno I, Hofer, Thomas P, Atkinson, Michael J, Anastasov, Nataša
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.02.2022; MDPI
• Subjects: Brain cancer; Breast cancer; Cancer therapies; CD44 antigen; Cell Line, Tumor; Clinical trials; combination therapy; Enzyme inhibitors; Extracellular signal-regulated kinase; Flow cytometry; Gene expression; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - radiotherapy; glioblastoma-derived spheres; Glucose; Growth factors; HDAC inhibitor; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Humans; Kinases; MAP kinase; MEK inhibitor; Mitogen-Activated Protein Kinase Kinases; Neoplasm Recurrence, Local; Nestin; Phenotypes; Protein Kinase Inhibitors - pharmacology; Radiation; Spheres; Stem cells; Temozolomide; Temozolomide - pharmacology; Tumors; Western blotting; United Kingdom > UK; United States > US; Germany; HDAC inhibitor; combination therapy; MEK inhibitor; glioblastoma; radiation; glioblastoma-derived spheres
• DOI: 10.3390/cells11050775
• ISSN: 2073-4409

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.