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...

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Veröffentlicht in:Nature communications Jg. 7; H. 1; S. 12308
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 25.07.2016
Nature Publishing Group
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Animals
Antimalarials - pharmacology
Atovaquone - pharmacology
Biguanides - pharmacology
Cancer therapies
Clinical outcomes
Drugs
Electron Transport Complex III - metabolism
FDA approval
High-Throughput Screening Assays
Humanities and Social Sciences
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Malaria
Mice, Inbred BALB C
Mice, Nude
multidisciplinary
Oncology
Oxygen consumption
Oxygen Consumption - drug effects
Pyrimidines - biosynthesis
Radiation therapy
Radiation Tolerance - drug effects
Science
Science (multidisciplinary)
Signal transduction
Spheroids, Cellular - drug effects
Spheroids, Cellular - metabolism
Spheroids, Cellular - pathology
Tumor Cells, Cultured
Tumor Hypoxia - drug effects
Tumors
ISSN:2041-1723, 2041-1723
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Zusammenfassung: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. Tumour hypoxia reduces the efficacy of radiotherapy. Starting from a drug screen, here the authors demonstrate that the anti-malarial, atovaquone, reduces the oxygen consumption rate of cancer cells by inhibition of mitochondrial complex III and sensitises to radiotherapy by reducing tumour hypoxia.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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These authors contributed equally to this work.
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms12308