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Tideglusib attenuates growth of neuroblastoma cancer stem/progenitor cells in vitro and in vivo by specifically targeting GSK-3β

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Abstract

Background

Neuroblastoma (NB) is the most frequently diagnosed extracranial solid tumor among the pediatric population. It is an embryonic tumor with high relapse rates pertaining to the presence of dormant slowly dividing cancer stem cells (CSC) within the tumor bulk that are responsible for therapy resistance. Therefore, there is a dire need to develop new therapeutic approaches that specifically target NB CSCs. Glycogen synthase kinase (GSK)-3β is a serine/threonine kinase that represents a common signaling node at the intersection of many pathways implicated in NB CSCs. GSK-3β sustains the survival and maintenance of CSCs and renders them insensitive to chemotherapeutic agents and radiation.

Methods

In our study, we aimed at evaluating the potential anti-tumor effect of Tideglusib (TDG), an irreversible GSK-3β inhibitor drug, on three human NB cell lines, SK-N-SH, SH-SY5Y, and IMR-32.

Results

Our results showed that TDG significantly reduced cell proliferation, viability, and migration of the NB cells, in a dose- and time-dependent manner, and also significantly hindered the neurospheres formation eradicating the self-renewal ability of highly resistant CSCs. Besides, TDG potently reduced CD133 cancer stem cell marker expression in both SH-SY5Y cells and G1 spheres. Lastly, TDG inhibited NB tumor growth and progression in vivo.

Conclusion

Collectively, we concluded that TDG could serve as an effective treatment capable of targeting the NB CSCs and hence overcoming therapy resistance. Yet, future studies are warranted to further investigate its potential role in NB and decipher the subcellular and molecular mechanisms underlying this role.

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Acknowledgements

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) (Grant no. HH2020), and the Medical Practice Plan (MPP) at the American University of Beirut – Faculty of Medicine (AUB-FM) (to WAK) (Grant no. WAK2020). 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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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. Mohamad K. Elajami

    Present address: Department of Internal Medicine, Mount Sinai Medical Center, Miami Beach, FL, USA

  4. Hisham F. Bahmad, Reda M. Chalhoub and Hayat Harati have contributed equally to this work as co-first authors.

  5. Georges Daoud, 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, Beirut, Lebanon

    Hisham F. Bahmad, Reda M. Chalhoub, Jolie Bou-Gharios, Sahar Assi, Farah Ballout, Alissar Monzer, Hiba Msheik, Tarek Araji, Mohamad K. Elajami, Paola Ghanem, Farah Chamaa, Georges Daoud & Wassim Abou-Kheir

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

    Hisham F. Bahmad, Hayat Harati, Jolie Bou-Gharios & Youssef Fares

  3. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Humam Kadara

  4. School of Pharmacy, Department of Pharmaceutical Sciences, Lebanese American University, Byblos, Lebanon

    Tamara Abou-Antoun

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Contributions

HFB: project administration, supervision, formal analysis, investigation, methodology, writing—original draft preparation, validation. RMC: investigation, methodology, writing—original draft preparation, writing—reviewing and editing, validation. HH: project administration, resources, writing—reviewing and editing, supervision, validation, visualization. JBG, AM and HM: investigation, methodology, writing—original draft preparation. SA and TA: investigation, methodology, writing—reviewing and editing. FB: investigation, methodology, writing—original draft preparation. MKE: original draft preparation. PG, FC and TAA: writing—reviewing and editing. HK: data curation, writing—reviewing and editing. GD: project administration, 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, writing—reviewing and editing, validation, visualization.

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Correspondence to Georges Daoud or Youssef Fares.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This study was approved by the Institutional Animal Care and Utilization Committee (IACUC) of the American University of Beirut. We also followed the ARRIVE guidelines (https://www.nc3rs.org.uk/arrive-guidelines) for animal researches.

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Bahmad, H.F., Chalhoub, R.M., Harati, H. et al. Tideglusib attenuates growth of neuroblastoma cancer stem/progenitor cells in vitro and in vivo by specifically targeting GSK-3β. Pharmacol. Rep 73, 211–226 (2021). https://doi.org/10.1007/s43440-020-00162-7

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