Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Bliss Street, DTS Bldg, Room 116-B, Riad el Solh, PO Box 110236/41, Beirut, 1107-2020, Lebanon.
Chair of Neurosurgery Department, Faculty of Medicine, Neuroscience Research Center, Lebanese University, Beirut, Lebanon.
Pharmacol Rep. 2021 Feb;73(1):227-239. doi: 10.1007/s43440-020-00180-5. Epub 2020 Nov 2.
Glioblastoma multiforme (GBM), a stage IV astrocytoma, is the most common brain malignancy among adults. Conventional treatments of surgical resection followed by radio and/or chemotherapy fail to completely eradicate the tumor. Resistance to the currently available therapies is mainly attributed to a subpopulation of cancer stem cells (CSCs) present within the tumor bulk that self-renew leading to tumor relapse with time. Therefore, identification of characteristic markers specific to these cells is crucial for the development of targeted therapies. Glycogen synthase kinase 3 (GSK-3), a serine-threonine kinase, is deregulated in a wide range of diseases, including cancer. In GBM, GSK-3β is overexpressed and its suppression in vitro has been shown to induce apoptosis of cancer cells.
In our study, we assessed the effect of GSK-3β inhibition with Tideglusib (TDG), an irreversible non-ATP competitive inhibitor, using two human GBM cell lines, U-251 MG and U-118 MG. In addition, we combined TDG with radiotherapy to assess whether this inhibition enhances the effect of standard treatment.
Our results showed that TDG significantly reduced cell proliferation, cell viability, and migration of both GBM cell lines in a dose- and time-dependent manner in vitro. Treatment with TDG alone and in combination with radiation significantly decreased the colony formation of U-251 MG cells and the sphere formation of both cell lines, by targeting and reducing their glioblastoma cancer stem-like cells (GSCs) population. Finally, cells treated with TDG showed an increased level of unrepaired radio-induced DNA damage and, thus, became sensitized toward radiation.
In conclusion, TDG has proven its effectiveness in targeting the cancerous properties of GBM in vitro and may, hence, serve as a potential adjuvant radio-therapeutic agent to better target this deadly tumor.
多形性胶质母细胞瘤（GBM）是一种 IV 级星形细胞瘤，是成年人中最常见的脑恶性肿瘤。手术切除后辅以放射和/或化疗的常规治疗方法无法完全根除肿瘤。目前可用的治疗方法的耐药性主要归因于肿瘤块内存在的一小部分癌症干细胞（CSC），这些细胞自我更新，随着时间的推移导致肿瘤复发。因此，鉴定这些细胞特有的特征标志物对于开发靶向治疗至关重要。糖原合成酶激酶 3（GSK-3）是一种丝氨酸-苏氨酸激酶，在包括癌症在内的广泛疾病中失调。在 GBM 中，GSK-3β过表达，体外抑制其表达已被证明可诱导癌细胞凋亡。
在我们的研究中，我们使用两种人 GBM 细胞系 U-251 MG 和 U-118 MG，评估了使用不可逆非 ATP 竞争性抑制剂 Tideglusib（TDG）抑制 GSK-3β 的效果。此外，我们将 TDG 与放射治疗相结合，以评估这种抑制是否增强标准治疗的效果。
我们的结果表明，TDG 以剂量和时间依赖的方式显著降低了两种 GBM 细胞系的细胞增殖、细胞活力和迁移。单独使用 TDG 以及与放射治疗联合使用，通过靶向和减少其胶质母细胞瘤癌症干细胞样细胞（GSCs）群体，显著降低了 U-251 MG 细胞的集落形成和两种细胞系的球体形成。最后，用 TDG 处理的细胞显示出未修复的放射性诱导的 DNA 损伤水平增加，因此对辐射变得敏感。
总之，TDG 已被证明在体外靶向 GBM 的致癌特性方面有效，因此可作为潜在的辅助放射治疗剂，以更好地靶向这种致命肿瘤。
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