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DIPG-09. ATOVAQUONE RADIOSENSITISES DIFFUSE MIDLINE GLIOMAS BY INHIBITING MITOCHONDRIAL METABOLISM AND HYPOXIA
Diffuse Midline Glioma (DMG) is a uniformly fatal paediatric brainstem tumour with median survival of less than 1 year. Radiotherapy has been the only effective treatment for decades, but most DMGs recur within several months due to radioresistance. The hypoxic tumour microenvironment, a main featur...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259914/ http://dx.doi.org/10.1093/neuonc/noad073.056 |
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author | Mudassar, Faiqa Chang, Cecilia Ing, Prunella Nguyen, Sandy Cook, Kristina M Warnken, Zachary N O’Neill, Geraldine Shen, Han Hau, Eric |
author_facet | Mudassar, Faiqa Chang, Cecilia Ing, Prunella Nguyen, Sandy Cook, Kristina M Warnken, Zachary N O’Neill, Geraldine Shen, Han Hau, Eric |
author_sort | Mudassar, Faiqa |
collection | PubMed |
description | Diffuse Midline Glioma (DMG) is a uniformly fatal paediatric brainstem tumour with median survival of less than 1 year. Radiotherapy has been the only effective treatment for decades, but most DMGs recur within several months due to radioresistance. The hypoxic tumour microenvironment, a main feature of solid tumours including gliomas, is a major contributor to radioresistance and impedes the efficacy of radiotherapy. Therefore, alleviating tumour hypoxia to enhance the effectiveness of radiotherapy is a therapeutic strategy to improve survival outcomes of DMG patients. Here, our strategy is to decrease the oxygen consumption rate (OCR) of DMG cells by targeting their mitochondria, which in turn will alleviate hypoxia by sparing more oxygen and subsequently improve the radiosensitivity of DMG cells. Specifically, we performed a high-throughput screening to identify potent OCR inhibitors using a library of 1963 FDA-approved drugs. The most promising OCR inhibitor identified was atovaquone, a drug used for treatment of pneumocystis pneumonia and malaria. We found that atovaquone inhibited mitochondrial metabolism of DMG cells by specifically targeting the mitochondrial complex III. It induced the formation of mitochondrial reactive oxygen species suggesting that it increases oxidative stress. It alleviated hypoxia and decreased the expression of hypoxia-inducible factor-1a in several 3-dimensional DMG neurospheres and improved the radiosensitivity of a range of DMG cultures. To overcome the issues of poor bioavailability of commercially available atovaquone resulting in low therapeutically effective brain concentrations, we tested its efficacy against the amorphous solid dispersion (ASD) atovaquone formulation which appears to enhance the atovaquone levels in the brain. We found that both the formulations inhibited OCR and hypoxia at similar doses and improved the radiosensitivity of DMG. With these promising findings, our further work is assessing the in vivo efficacies of commercially available atovaquone and ASD atovaquone formulation using orthotopic DMG models. |
format | Online Article Text |
id | pubmed-10259914 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-102599142023-06-13 DIPG-09. ATOVAQUONE RADIOSENSITISES DIFFUSE MIDLINE GLIOMAS BY INHIBITING MITOCHONDRIAL METABOLISM AND HYPOXIA Mudassar, Faiqa Chang, Cecilia Ing, Prunella Nguyen, Sandy Cook, Kristina M Warnken, Zachary N O’Neill, Geraldine Shen, Han Hau, Eric Neuro Oncol Final Category: Diffuse Intrinsic Pontine Glioma/Diffuse Midline Gliomas - DPIG Diffuse Midline Glioma (DMG) is a uniformly fatal paediatric brainstem tumour with median survival of less than 1 year. Radiotherapy has been the only effective treatment for decades, but most DMGs recur within several months due to radioresistance. The hypoxic tumour microenvironment, a main feature of solid tumours including gliomas, is a major contributor to radioresistance and impedes the efficacy of radiotherapy. Therefore, alleviating tumour hypoxia to enhance the effectiveness of radiotherapy is a therapeutic strategy to improve survival outcomes of DMG patients. Here, our strategy is to decrease the oxygen consumption rate (OCR) of DMG cells by targeting their mitochondria, which in turn will alleviate hypoxia by sparing more oxygen and subsequently improve the radiosensitivity of DMG cells. Specifically, we performed a high-throughput screening to identify potent OCR inhibitors using a library of 1963 FDA-approved drugs. The most promising OCR inhibitor identified was atovaquone, a drug used for treatment of pneumocystis pneumonia and malaria. We found that atovaquone inhibited mitochondrial metabolism of DMG cells by specifically targeting the mitochondrial complex III. It induced the formation of mitochondrial reactive oxygen species suggesting that it increases oxidative stress. It alleviated hypoxia and decreased the expression of hypoxia-inducible factor-1a in several 3-dimensional DMG neurospheres and improved the radiosensitivity of a range of DMG cultures. To overcome the issues of poor bioavailability of commercially available atovaquone resulting in low therapeutically effective brain concentrations, we tested its efficacy against the amorphous solid dispersion (ASD) atovaquone formulation which appears to enhance the atovaquone levels in the brain. We found that both the formulations inhibited OCR and hypoxia at similar doses and improved the radiosensitivity of DMG. With these promising findings, our further work is assessing the in vivo efficacies of commercially available atovaquone and ASD atovaquone formulation using orthotopic DMG models. Oxford University Press 2023-06-12 /pmc/articles/PMC10259914/ http://dx.doi.org/10.1093/neuonc/noad073.056 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Final Category: Diffuse Intrinsic Pontine Glioma/Diffuse Midline Gliomas - DPIG Mudassar, Faiqa Chang, Cecilia Ing, Prunella Nguyen, Sandy Cook, Kristina M Warnken, Zachary N O’Neill, Geraldine Shen, Han Hau, Eric DIPG-09. ATOVAQUONE RADIOSENSITISES DIFFUSE MIDLINE GLIOMAS BY INHIBITING MITOCHONDRIAL METABOLISM AND HYPOXIA |
title | DIPG-09. ATOVAQUONE RADIOSENSITISES DIFFUSE MIDLINE GLIOMAS BY INHIBITING MITOCHONDRIAL METABOLISM AND HYPOXIA |
title_full | DIPG-09. ATOVAQUONE RADIOSENSITISES DIFFUSE MIDLINE GLIOMAS BY INHIBITING MITOCHONDRIAL METABOLISM AND HYPOXIA |
title_fullStr | DIPG-09. ATOVAQUONE RADIOSENSITISES DIFFUSE MIDLINE GLIOMAS BY INHIBITING MITOCHONDRIAL METABOLISM AND HYPOXIA |
title_full_unstemmed | DIPG-09. ATOVAQUONE RADIOSENSITISES DIFFUSE MIDLINE GLIOMAS BY INHIBITING MITOCHONDRIAL METABOLISM AND HYPOXIA |
title_short | DIPG-09. ATOVAQUONE RADIOSENSITISES DIFFUSE MIDLINE GLIOMAS BY INHIBITING MITOCHONDRIAL METABOLISM AND HYPOXIA |
title_sort | dipg-09. atovaquone radiosensitises diffuse midline gliomas by inhibiting mitochondrial metabolism and hypoxia |
topic | Final Category: Diffuse Intrinsic Pontine Glioma/Diffuse Midline Gliomas - DPIG |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10259914/ http://dx.doi.org/10.1093/neuonc/noad073.056 |
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