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The potential use of tideglusib as an adjuvant radio-therapeutic treatment for glioblastoma multiforme cancer stem-like cells

Pharmacological Reports volume 73, pages 227–239 (2021)Cite this article

A Correction to this article was published on 01 December 2020

This article has been updated

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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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Availability of data and material (data transparency)

All data generated or analyzed during this study were included in this published article.

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Acknowledgments

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.

Funding

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.

Author information

Author notes

  1. Hisham F. Bahmad

    Present address: Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA

  2. Reda M. Chalhoub

    Present address: Medical Scientist Training Program, College of Medicine, Medical University of South Carolina, Charleston, SC, USA

  3. Jolie Bou-Gharios, Sahar Assi and Hisham F. Bahmad have contributed equally to this work as co-first authors.

  4. Youssef Fares and Wassim Abou-Kheir have contributed equally to this work as joint senior authors.

Authors and Affiliations

  1. 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

    Jolie Bou-Gharios, Sahar Assi, Hisham F. Bahmad, Hussein Kharroubi, Tarek Araji, Reda M. Chalhoub, Farah Ballout & Wassim Abou-Kheir

  2. Chair of Neurosurgery Department, Faculty of Medicine, Neuroscience Research Center, Lebanese University, Beirut, Lebanon

    Jolie Bou-Gharios, Hayat Harati & Youssef Fares

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  1. Jolie Bou-Gharios
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Contributions

JBG: Formal analysis, Investigation, Methodology, Writing- Original draft preparation. SA: Formal analysis, Investigation, Methodology, Writing—Original draft preparation. HFB: Project administration, Supervision, Formal analysis, Investigation, Methodology, Writing- Reviewing and Editing. HK: Investigation, Methodology, Writing- Reviewing and Editing. TA: Investigation, Methodology, Writing- Reviewing and Editing. RMC: Investigation, Methodology, Writing- Reviewing and Editing, Validation. FB: Investigation, Methodology, Writing- Reviewing and Editing. HH: Resources, Funding acquisition, Writing—Reviewing and Editing, Supervision, Validation, Visualization. YF: Project administration, Funding acquisition, Writing- Reviewing and Editing, Supervision, Validation, Visualization. WAK: Conceptualization, Project administration, Resources, Software, Supervision, Funding acquisition, Writing—Reviewing and Editing, Validation, Visualization.

Corresponding authors

Correspondence to Youssef Fares or Wassim Abou-Kheir.

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The original online version of this article was revised: The spelling of Youssef Fares’ name was incorrect.

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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

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Keywords

  • Glioblastoma multiforme
  • Tideglusib
  • GSK-3β
  • Radiation
  • Cancer stem cells
  • Glioblastoma stem-like cells
  • Sphere-formation assay