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.
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.
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.
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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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) (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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The authors declare that they have no conflict of interest.
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
- Cancer stem cells
- Targeted therapy