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The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling

BACKGROUND: Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 and IDH2) mutations (IDHmut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations inc...

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Autores principales: Yamashita, Alex Shimura, da Costa Rosa, Marina, Stumpo, Vittorio, Rais, Rana, Slusher, Barbara S, Riggins, Gregory J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920530/
https://www.ncbi.nlm.nih.gov/pubmed/33681764
http://dx.doi.org/10.1093/noajnl/vdaa149
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author Yamashita, Alex Shimura
da Costa Rosa, Marina
Stumpo, Vittorio
Rais, Rana
Slusher, Barbara S
Riggins, Gregory J
author_facet Yamashita, Alex Shimura
da Costa Rosa, Marina
Stumpo, Vittorio
Rais, Rana
Slusher, Barbara S
Riggins, Gregory J
author_sort Yamashita, Alex Shimura
collection PubMed
description BACKGROUND: Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 and IDH2) mutations (IDHmut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations increase reliance on glutamine metabolism, suggesting a potential vulnerability. In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth. MATERIAL AND METHODS: We performed cell growth, cell cycle, and protein expression in glutamine deprived or Glutaminase (GLS) gene silenced glioma cells. We tested the effect of JHU-083 on cell proliferation, metabolism, and mTOR signaling in cancer cell lines. An orthotopic IDH1R132H glioma model was used to test the efficacy of JHU-083 in vivo. RESULTS: Glutamine deprivation and GLS gene silencing reduced glioma cell proliferation in vitro in glioma cells. JHU-083 reduced glioma cell growth in vitro, modulated cell metabolism, and disrupted mTOR signaling and downregulated Cyclin D1 protein expression, through a mechanism independent of TSC2 modulation and glutaminolysis. IDH1R132H isogenic cells preferentially reduced cell growth and mTOR signaling downregulation. In addition, guanine supplementation partially rescued IDHmut glioma cell growth, mTOR signaling, and Cyclin D1 protein expression in vitro. Finally, JHU-083 extended survival in an intracranial IDH1 mut glioma model and reduced intracranial pS6 protein expression. CONCLUSION: Targeting glutamine metabolism with JHU-083 showed efficacy in preclinical models of IDHmut glioma and measurably decreased mTOR signaling.
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spelling pubmed-79205302021-03-04 The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling Yamashita, Alex Shimura da Costa Rosa, Marina Stumpo, Vittorio Rais, Rana Slusher, Barbara S Riggins, Gregory J Neurooncol Adv Basic and Translational Investigations BACKGROUND: Metabolic reprogramming is a common feature in cancer, and it is critical to facilitate cancer cell growth. Isocitrate Dehydrogenase 1/2 (IDH1 and IDH2) mutations (IDHmut) are the most common genetic alteration in glioma grade II and III and secondary glioblastoma and these mutations increase reliance on glutamine metabolism, suggesting a potential vulnerability. In this study, we tested the hypothesis that the brain penetrant glutamine antagonist prodrug JHU-083 reduces glioma cell growth. MATERIAL AND METHODS: We performed cell growth, cell cycle, and protein expression in glutamine deprived or Glutaminase (GLS) gene silenced glioma cells. We tested the effect of JHU-083 on cell proliferation, metabolism, and mTOR signaling in cancer cell lines. An orthotopic IDH1R132H glioma model was used to test the efficacy of JHU-083 in vivo. RESULTS: Glutamine deprivation and GLS gene silencing reduced glioma cell proliferation in vitro in glioma cells. JHU-083 reduced glioma cell growth in vitro, modulated cell metabolism, and disrupted mTOR signaling and downregulated Cyclin D1 protein expression, through a mechanism independent of TSC2 modulation and glutaminolysis. IDH1R132H isogenic cells preferentially reduced cell growth and mTOR signaling downregulation. In addition, guanine supplementation partially rescued IDHmut glioma cell growth, mTOR signaling, and Cyclin D1 protein expression in vitro. Finally, JHU-083 extended survival in an intracranial IDH1 mut glioma model and reduced intracranial pS6 protein expression. CONCLUSION: Targeting glutamine metabolism with JHU-083 showed efficacy in preclinical models of IDHmut glioma and measurably decreased mTOR signaling. Oxford University Press 2020-10-29 /pmc/articles/PMC7920530/ /pubmed/33681764 http://dx.doi.org/10.1093/noajnl/vdaa149 Text en © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Basic and Translational Investigations
Yamashita, Alex Shimura
da Costa Rosa, Marina
Stumpo, Vittorio
Rais, Rana
Slusher, Barbara S
Riggins, Gregory J
The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling
title The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling
title_full The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling
title_fullStr The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling
title_full_unstemmed The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling
title_short The glutamine antagonist prodrug JHU-083 slows malignant glioma growth and disrupts mTOR signaling
title_sort glutamine antagonist prodrug jhu-083 slows malignant glioma growth and disrupts mtor signaling
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920530/
https://www.ncbi.nlm.nih.gov/pubmed/33681764
http://dx.doi.org/10.1093/noajnl/vdaa149
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