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.
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We would like to thank all members in the Abou-Kheir’s Laboratory (The WAK Lab) for their help on this work. In addition, we would like to thank members of the core facilities in the DTS Building at the American University of Beirut (AUB) for their help and support.
This work was supported by the Lebanese National Council for Scientific Research Grant Research Program (LNCSR-GRP) (Grant # 01-10-17; to YF), the Neuroscience Research Center, Faculty of Medicine, Lebanese University (LU) (to HH), and the Medical Practice Plan (MPP) at the American University of Beirut – Faculty of Medicine (AUB-FM) (to WAK). Funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
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Bou-Gharios, J., Assi, S., Bahmad, H.F. et al. The potential use of tideglusib as an adjuvant radio-therapeutic treatment for glioblastoma multiforme cancer stem-like cells. Pharmacol. Rep 73, 227–239 (2021). https://doi.org/10.1007/s43440-020-00180-5
- Glioblastoma multiforme
- Cancer stem cells
- Glioblastoma stem-like cells
- Sphere-formation assay