The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia

Thomas M. Ashton, Emmanouil Fokas, Leoni A. Kunz-Schughart, Lisa K. Folkes, Selvakumar Anbalagan, Melanie Huether, Catherine J. Kelly, Giacomo Pirovano, Francesca M. Buffa, Ester M. Hammond, Michael Stratford, Ruth J. Muschel, Geoff S. Higgins () and William Gillies McKenna ()
Additional contact information
Thomas M. Ashton: CRUK/MRC Oxford Institute for Radiation Oncology
Emmanouil Fokas: CRUK/MRC Oxford Institute for Radiation Oncology
Leoni A. Kunz-Schughart: CRUK/MRC Oxford Institute for Radiation Oncology
Lisa K. Folkes: CRUK/MRC Oxford Institute for Radiation Oncology
Selvakumar Anbalagan: CRUK/MRC Oxford Institute for Radiation Oncology
Melanie Huether: OncoRay – National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden, and Helmholtz-Zentrum Dresden–Rossendorf, Institute of Radiooncology
Catherine J. Kelly: CRUK/MRC Oxford Institute for Radiation Oncology
Giacomo Pirovano: CRUK/MRC Oxford Institute for Radiation Oncology
Francesca M. Buffa: CRUK/MRC Oxford Institute for Radiation Oncology
Ester M. Hammond: CRUK/MRC Oxford Institute for Radiation Oncology
Michael Stratford: CRUK/MRC Oxford Institute for Radiation Oncology
Ruth J. Muschel: CRUK/MRC Oxford Institute for Radiation Oncology
Geoff S. Higgins: CRUK/MRC Oxford Institute for Radiation Oncology
William Gillies McKenna: CRUK/MRC Oxford Institute for Radiation Oncology

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12308

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