MCT1 Inhibitor AZD3965 Increases Mitochondrial Metabolism, Facilitating Combination Therapy and Noninvasive Magnetic Resonance Spectroscopy
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- Mounia Beloueche-Babari
- 1Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
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- Slawomir Wantuch
- 1Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
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- Teresa Casals Galobart
- 1Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
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- Markella Koniordou
- 1Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
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- Harold G. Parkes
- 1Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
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- Vaitha Arunan
- 1Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
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- Yuen-Li Chung
- 1Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
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- Thomas R. Eykyn
- 1Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
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- Paul D. Smith
- 2AstraZeneca, Cancer Biosciences, Cancer Research UK Cambridge Institute, Cambridge, United Kingdom.
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- Martin O. Leach
- 1Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London and The Royal Marsden NHS Foundation Trust, London, United Kingdom.
書誌事項
- 公開日
- 2017-10-31
- DOI
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- 10.1158/0008-5472.can-16-2686
- 公開者
- American Association for Cancer Research (AACR)
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>Monocarboxylate transporters (MCT) modulate tumor cell metabolism and offer promising therapeutic targets for cancer treatment. Understanding the impact of MCT blockade on tumor cell metabolism may help develop combination strategies or identify pharmacodynamic biomarkers to support the clinical development of MCT inhibitors now in clinical trials. In this study, we assessed the impact of the MCT1 inhibitor AZD3965 on cancer cell metabolism in vitro and in vivo. Exposing human lymphoma and colon carcinoma cells to AZD3965 increased MCT4-dependent accumulation of intracellular lactate, inhibiting monocarboxylate influx and efflux. AZD3965 also increased the levels of TCA cycle–related metabolites and 13C-glucose mitochondrial metabolism, enhancing oxidative pyruvate dehydrogenase and anaplerotic pyruvate carboxylase fluxes. Increased mitochondrial metabolism was necessary to maintain cell survival under drug stress. These effects were counteracted by coadministration of the mitochondrial complex I inhibitor metformin and the mitochondrial pyruvate carrier inhibitor UK5099. Improved bioenergetics were confirmed in vivo after dosing with AZD3965 in mouse xenograft models of human lymphoma. Our results reveal new metabolic consequences of MCT1 inhibition that might be exploited for therapeutic and pharmacodynamic purposes. Cancer Res; 77(21); 5913–24. ©2017 AACR.</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 77 (21), 5913-5924, 2017-10-31
American Association for Cancer Research (AACR)
