Cargando…

The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia

Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with thi...

Descripción completa

Detalles Bibliográficos
Autores principales: Ashton, Thomas M., Fokas, Emmanouil, Kunz-Schughart, Leoni A., Folkes, Lisa K., Anbalagan, Selvakumar, Huether, Melanie, Kelly, Catherine J., Pirovano, Giacomo, Buffa, Francesca M., Hammond, Ester M., Stratford, Michael, Muschel, Ruth J., Higgins, Geoff S., McKenna, William Gillies
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962491/
https://www.ncbi.nlm.nih.gov/pubmed/27453292
http://dx.doi.org/10.1038/ncomms12308
_version_ 1782444847502721024
author Ashton, Thomas M.
Fokas, Emmanouil
Kunz-Schughart, Leoni A.
Folkes, Lisa K.
Anbalagan, Selvakumar
Huether, Melanie
Kelly, Catherine J.
Pirovano, Giacomo
Buffa, Francesca M.
Hammond, Ester M.
Stratford, Michael
Muschel, Ruth J.
Higgins, Geoff S.
McKenna, William Gillies
author_facet Ashton, Thomas M.
Fokas, Emmanouil
Kunz-Schughart, Leoni A.
Folkes, Lisa K.
Anbalagan, Selvakumar
Huether, Melanie
Kelly, Catherine J.
Pirovano, Giacomo
Buffa, Francesca M.
Hammond, Ester M.
Stratford, Michael
Muschel, Ruth J.
Higgins, Geoff S.
McKenna, William Gillies
author_sort Ashton, Thomas M.
collection PubMed
description Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy.
format Online
Article
Text
id pubmed-4962491
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-49624912016-09-06 The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia Ashton, Thomas M. Fokas, Emmanouil Kunz-Schughart, Leoni A. Folkes, Lisa K. Anbalagan, Selvakumar Huether, Melanie Kelly, Catherine J. Pirovano, Giacomo Buffa, Francesca M. Hammond, Ester M. Stratford, Michael Muschel, Ruth J. Higgins, Geoff S. McKenna, William Gillies Nat Commun Article Tumour hypoxia renders cancer cells resistant to cancer therapy, resulting in markedly worse clinical outcomes. To find clinical candidate compounds that reduce hypoxia in tumours, we conduct a high-throughput screen for oxygen consumption rate (OCR) reduction and identify a number of drugs with this property. For this study we focus on the anti-malarial, atovaquone. Atovaquone rapidly decreases the OCR by more than 80% in a wide range of cancer cell lines at pharmacological concentrations. In addition, atovaquone eradicates hypoxia in FaDu, HCT116 and H1299 spheroids. Similarly, it reduces hypoxia in FaDu and HCT116 xenografts in nude mice, and causes a significant tumour growth delay when combined with radiation. Atovaquone is a ubiquinone analogue, and decreases the OCR by inhibiting mitochondrial complex III. We are now undertaking clinical studies to assess whether atovaquone reduces tumour hypoxia in patients, thereby increasing the efficacy of radiotherapy. Nature Publishing Group 2016-07-25 /pmc/articles/PMC4962491/ /pubmed/27453292 http://dx.doi.org/10.1038/ncomms12308 Text en Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Ashton, Thomas M.
Fokas, Emmanouil
Kunz-Schughart, Leoni A.
Folkes, Lisa K.
Anbalagan, Selvakumar
Huether, Melanie
Kelly, Catherine J.
Pirovano, Giacomo
Buffa, Francesca M.
Hammond, Ester M.
Stratford, Michael
Muschel, Ruth J.
Higgins, Geoff S.
McKenna, William Gillies
The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia
title The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia
title_full The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia
title_fullStr The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia
title_full_unstemmed The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia
title_short The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia
title_sort anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4962491/
https://www.ncbi.nlm.nih.gov/pubmed/27453292
http://dx.doi.org/10.1038/ncomms12308
work_keys_str_mv AT ashtonthomasm theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT fokasemmanouil theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT kunzschughartleonia theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT folkeslisak theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT anbalaganselvakumar theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT huethermelanie theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT kellycatherinej theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT pirovanogiacomo theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT buffafrancescam theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT hammondesterm theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT stratfordmichael theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT muschelruthj theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT higginsgeoffs theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT mckennawilliamgillies theantimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT ashtonthomasm antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT fokasemmanouil antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT kunzschughartleonia antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT folkeslisak antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT anbalaganselvakumar antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT huethermelanie antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT kellycatherinej antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT pirovanogiacomo antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT buffafrancescam antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT hammondesterm antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT stratfordmichael antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT muschelruthj antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT higginsgeoffs antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia
AT mckennawilliamgillies antimalarialatovaquoneincreasesradiosensitivitybyalleviatingtumourhypoxia