title: The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia.
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.
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Ashton
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.|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, Dresden, P.O. Box 41, 01307, Germany.
authors.forename: Leoni A
authors.initials: LA
authors.lastname: Kunz-Schughart
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Folkes
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Selvakumar
authors.identifier: 0000-0001-6128-7998
authors.initials: S
authors.lastname: Anbalagan
authors.affiliation: 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, Dresden, P.O. Box 41, 01307, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Huether
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Kelly
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Pirovano
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Stratford
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Ruth J
authors.initials: RJ
authors.lastname: Muschel
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Geoff S
authors.initials: GS
authors.lastname: Higgins
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: William Gillies
authors.initials: WG
authors.lastname: McKenna
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D053626:Atovaquone / Q000494:pharmacology*; D001645:Biguanides / Q000494:pharmacology; D014450:Electron Transport Complex III / Q000378:metabolism; D057166:High-Throughput Screening Assays; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010101:Oxygen Consumption / Q000187:drug effects; D011743:Pyrimidines / Q000096:biosynthesis; D011836:Radiation Tolerance / Q000187:drug effects*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D000072258:Tumor Hypoxia / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D001645:Biguanides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011743:Pyrimidines; D014450:Electron Transport Complex III; C030986:pyrimidine; D053626:Atovaquone