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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Vydáno v:	Nature communications Ročník 7; číslo 1; s. 12308
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 25.07.2016 Nature Publishing Group Nature Portfolio
Témata:	13/106 13/51 14 14/63 631/67/1059 631/67/2327 64/60 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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 These authors contributed equally to this work.
ISSN:	2041-1723 2041-1723
DOI:	10.1038/ncomms12308