title: Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations: Princess Margaret Cancer Centre and Radiation Medicine Program, University Health Network; Institute of Medical Science, Department of Radiation Oncology, Faculty of Medicine, Department of Medical Biophysics, University of Toronto; Selective Therapies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; and Department of Radiation Oncology (Maastro Lab), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Vanessa E
authors.initials: VE
authors.lastname: Zannella
authors.forename: Alan
authors.initials: A
authors.lastname: Dal Pra
authors.forename: Hala
authors.initials: H
authors.lastname: Muaddi
authors.forename: Trevor D
authors.initials: TD
authors.lastname: McKee
authors.forename: Shawn
authors.initials: S
authors.lastname: Stapleton
authors.forename: Jenna
authors.initials: J
authors.lastname: Sykes
authors.forename: Rachel
authors.initials: R
authors.lastname: Glicksman
authors.forename: Selim
authors.initials: S
authors.lastname: Chaib
authors.forename: Paul
authors.initials: P
authors.lastname: Zamiara
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.forename: Bradly G
authors.initials: BG
authors.lastname: Wouters
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
authors.forename: Marianne
authors.initials: M
authors.lastname: Koritzinsky
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D042967:Electron Transport Complex I / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D008687:Metformin; D042967:Electron Transport Complex I; D010100:Oxygen