Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response
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- Vanessa E. Zannella
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Alan Dal Pra
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Hala Muaddi
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Trevor D. McKee
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Shawn Stapleton
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Jenna Sykes
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Rachel Glicksman
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Selim Chaib
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Paul Zamiara
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Michael Milosevic
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Bradly G. Wouters
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Robert G. Bristow
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
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- Marianne Koritzinsky
- Authors' Affiliations: 1Princess Margaret Cancer Centre and 2Radiation Medicine Program, University Health Network; 3Institute of Medical Science, 4Department of Radiation Oncology, 5Faculty of Medicine, 6Department of Medical Biophysics, University of Toronto; 7Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and 8Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
抄録
<jats:title>Abstract</jats:title> <jats:p>Purpose: Tumor hypoxia is a negative prognostic factor in multiple cancers, due in part to its role in causing resistance to radiotherapy. Hypoxia arises in tumor regions distal to blood vessels as oxygen is consumed by more proximal tumor cells. Reducing the rate of oxygen consumption is therefore a potential strategy to reduce tumor hypoxia. We hypothesized that the anti-diabetic drug metformin, which reduces oxygen consumption through inhibition of mitochondrial complex I, would improve radiation response by increasing tumor oxygenation.</jats:p> <jats:p>Experimental Design: Tumor hypoxia was measured in xenografts before and after metformin treatment using 2-nitroimidazole hypoxia markers quantified by immunohistochemistry (IHC), flow cytometry, and positron emission tomography (PET) imaging. Radiation response was determined by tumor growth delay and clonogenic survival in xenografts with and without administration of metformin. The impact of metformin use on outcome was assessed in 504 patients with localized prostate cancer treated with curative-intent, image-guided radiotherapy (IGRT) from 1996 to 2012. Three-year biochemical relapse-free rates were assessed using the Kaplan–Meier method.</jats:p> <jats:p>Results: Metformin treatment significantly improved tumor oxygenation in two xenograft models as measured by IHC, flow cytometry, and PET imaging. Metformin also led to improved radiotherapy responses when mice were administered metformin immediately before irradiation. Clinically, metformin use was associated with an independent and significant decrease in early biochemical relapse rates (P = 0.0106).</jats:p> <jats:p>Conclusion: Our data demonstrate that metformin can improve tumor oxygenation and response to radiotherapy. Our study suggests that metformin may represent an effective and inexpensive means to improve radiotherapy outcome with an optimal therapeutic ratio. Clin Cancer Res; 19(24); 6741–50. ©2013 AACR.</jats:p>
収録刊行物
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- Clinical Cancer Research
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Clinical Cancer Research 19 (24), 6741-6750, 2013-12-15
American Association for Cancer Research (AACR)