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Specific Inhibition of GSK-3β by Tideglusib: Potential Therapeutic Target for Neuroblastoma Cancer Stem Cells

View ORCID ProfileHisham F. Bahmad, View ORCID ProfileReda M. Chalhoub, Hayat Harati, View ORCID ProfileJolie Bou-Gharios, Farah Ballout, Alissar Monzer, Hiba Msheik, Sahar Assi, Tarek Araji, Mohamad K. Elajami, Paola Ghanem, Farah Chamaa, Humam Kadara, Tamara Abou-Antoun, Georges Daoud, Youssef Fares, Wassim Abou-Kheir
doi: https://doi.org/10.1101/2020.02.18.953596
Hisham F. Bahmad
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
2Neuroscience Research Center, Faculty of Medicine, Lebanese University, Beirut, Lebanon
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  • ORCID record for Hisham F. Bahmad
Reda M. Chalhoub
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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  • ORCID record for Reda M. Chalhoub
Hayat Harati
2Neuroscience Research Center, Faculty of Medicine, Lebanese University, Beirut, Lebanon
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Jolie Bou-Gharios
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
2Neuroscience Research Center, Faculty of Medicine, Lebanese University, Beirut, Lebanon
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Farah Ballout
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Alissar Monzer
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Hiba Msheik
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Sahar Assi
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Tarek Araji
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Mohamad K. Elajami
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Paola Ghanem
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Farah Chamaa
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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Humam Kadara
3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Tamara Abou-Antoun
4School of Pharmacy, Department of Pharmaceutical Sciences, Lebanese American University, Byblos, Lebanon
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Georges Daoud
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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  • For correspondence: wa12@aub.edu.lb yfares@ul.edu.lb gd12@aub.edu.lb
Youssef Fares
2Neuroscience Research Center, Faculty of Medicine, Lebanese University, Beirut, Lebanon
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  • For correspondence: wa12@aub.edu.lb yfares@ul.edu.lb gd12@aub.edu.lb
Wassim Abou-Kheir
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
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  • For correspondence: wa12@aub.edu.lb yfares@ul.edu.lb gd12@aub.edu.lb
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Abstract

Neuroblastoma is an embryonic tumor that represents the most common extracranial solid tumor in children. Resistance to therapy is attributed, in part, to the persistence of a subpopulation of slowly dividing cancer stem cells (CSCs) within those tumors. Glycogen synthase kinase (GSK)-3β is an active proline-directed serine/threonine kinase, well-known to be involved in different signaling pathways entangled in the pathophysiology of neuroblastoma. This study aims to assess the potency of an irreversible GSK-3β inhibitor drug, Tideglusib (TDG), in suppressing proliferation, viability, and migration of human neuroblastoma cell lines, as well as its effects on their CSCs subpopulation in vitro and in vivo. Our results showed that treatment with TDG significantly reduced cell proliferation, viability, and migration of SK-N-SH and SH-SY5Y cells. TDG also significantly inhibited neurospheres formation capability in both cell lines, eradicating the self-renewal ability of highly resistant CSCs. Importantly, TDG potently inhibited neuroblastoma tumor growth and progression in vivo. In conclusion, TDG proved to be an effective in vitro and in vivo treatment for neuroblastoma cell lines and may hence serve as a potential adjuvant therapeutic agent for this aggressive nervous system tumor.

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  • Declarations of interest: none

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Specific Inhibition of GSK-3β by Tideglusib: Potential Therapeutic Target for Neuroblastoma Cancer Stem Cells
Hisham F. Bahmad, Reda M. Chalhoub, Hayat Harati, Jolie Bou-Gharios, Farah Ballout, Alissar Monzer, Hiba Msheik, Sahar Assi, Tarek Araji, Mohamad K. Elajami, Paola Ghanem, Farah Chamaa, Humam Kadara, Tamara Abou-Antoun, Georges Daoud, Youssef Fares, Wassim Abou-Kheir
bioRxiv 2020.02.18.953596; doi: https://doi.org/10.1101/2020.02.18.953596
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Specific Inhibition of GSK-3β by Tideglusib: Potential Therapeutic Target for Neuroblastoma Cancer Stem Cells
Hisham F. Bahmad, Reda M. Chalhoub, Hayat Harati, Jolie Bou-Gharios, Farah Ballout, Alissar Monzer, Hiba Msheik, Sahar Assi, Tarek Araji, Mohamad K. Elajami, Paola Ghanem, Farah Chamaa, Humam Kadara, Tamara Abou-Antoun, Georges Daoud, Youssef Fares, Wassim Abou-Kheir
bioRxiv 2020.02.18.953596; doi: https://doi.org/10.1101/2020.02.18.953596

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