Increasing radiosensitivity by alleviating tumour hypoxia: a drug screen reveals atovaquone as a clinical candidate
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 conducted a high throughput screen for oxygen consumption rate (OCR) reduction and identified a number...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Journal article |
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Nature Publishing Group
2016
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| _version_ | 1797092652955467776 |
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| author | Ashton, T Fokas, E Kunz-Schughart, L Folkes, L Anbalagan, S Huether, M Kelly, C Pirovano, G Buffa, F Hammond, E Stratford, M Muschel, R Higgins, G McKenna, W |
| author_facet | Ashton, T Fokas, E Kunz-Schughart, L Folkes, L Anbalagan, S Huether, M Kelly, C Pirovano, G Buffa, F Hammond, E Stratford, M Muschel, R Higgins, G McKenna, W |
| author_sort | Ashton, T |
| collection | OXFORD |
| 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 conducted a high throughput screen for oxygen consumption rate (OCR) reduction and identified a number of drugs with this property. For this study we focused on the antimalarial, 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 virtually eliminates 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. |
| first_indexed | 2024-03-07T03:49:05Z |
| format | Journal article |
| id | oxford-uuid:c0976293-ae5d-4422-95a2-d5cf0077bcd9 |
| institution | University of Oxford |
| last_indexed | 2024-03-07T03:49:05Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:c0976293-ae5d-4422-95a2-d5cf0077bcd92022-03-27T05:55:24ZIncreasing radiosensitivity by alleviating tumour hypoxia: a drug screen reveals atovaquone as a clinical candidateJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c0976293-ae5d-4422-95a2-d5cf0077bcd9Symplectic Elements at OxfordNature Publishing Group2016Ashton, TFokas, EKunz-Schughart, LFolkes, LAnbalagan, SHuether, MKelly, CPirovano, GBuffa, FHammond, EStratford, MMuschel, RHiggins, GMcKenna, WTumour 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 conducted a high throughput screen for oxygen consumption rate (OCR) reduction and identified a number of drugs with this property. For this study we focused on the antimalarial, 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 virtually eliminates 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. |
| spellingShingle | Ashton, T Fokas, E Kunz-Schughart, L Folkes, L Anbalagan, S Huether, M Kelly, C Pirovano, G Buffa, F Hammond, E Stratford, M Muschel, R Higgins, G McKenna, W Increasing radiosensitivity by alleviating tumour hypoxia: a drug screen reveals atovaquone as a clinical candidate |
| title | Increasing radiosensitivity by alleviating tumour hypoxia: a drug screen reveals atovaquone as a clinical candidate |
| title_full | Increasing radiosensitivity by alleviating tumour hypoxia: a drug screen reveals atovaquone as a clinical candidate |
| title_fullStr | Increasing radiosensitivity by alleviating tumour hypoxia: a drug screen reveals atovaquone as a clinical candidate |
| title_full_unstemmed | Increasing radiosensitivity by alleviating tumour hypoxia: a drug screen reveals atovaquone as a clinical candidate |
| title_short | Increasing radiosensitivity by alleviating tumour hypoxia: a drug screen reveals atovaquone as a clinical candidate |
| title_sort | increasing radiosensitivity by alleviating tumour hypoxia a drug screen reveals atovaquone as a clinical candidate |
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