Institute of Biological and Medical Imaging, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Institute of Radiation Biology, Helmholtz Center Munich, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Cells. 2022 Feb 23;11(5):775. doi: 10.3390/cells11050775.
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.
胶质母细胞瘤干细胞（GSLCs）限制了胶质母细胞瘤的有效治疗，并促进了治疗抵抗和肿瘤复发。我们使用联合辐射和药物筛选平台，测试了组蛋白去乙酰化酶抑制剂（HDACi）和 MAPK/ERK 激酶抑制剂（MEKi）与辐射联合使用对 GSLCs 的疗效。为了模拟干细胞样表型，使用胶质母细胞瘤衍生的球体，并使用 HDACi（MS-275）和 MEKi（TAK-733 或 trametinib）与 4 Gy 照射联合治疗。通过球体形成测定法研究联合放化疗后的球体形成能力，同时使用 Western blot 和流式细胞术分析治疗后 GSLC 标志物（CD44、Nestin 和 SOX2）的表达水平。联合放化疗治疗抑制了两种胶质母细胞瘤衍生球体的球体形成，以细胞系依赖性方式降低 GSLC 标志物的表达，并增加死亡细胞群体。最后，我们表明与标准的替莫唑胺和放射治疗相比，联合放射治疗更能有效降低 GSLC 标志物。这些结果表明，联合使用 HDAC 和 MEK 抑制与放射治疗可能为改善胶质母细胞瘤的治疗提供新策略。
