Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

Vanessa E. Zannella, Alan Dal Pra, Hala Muaddi, Trevor D. McKee, Shawn Stapleton, Jenna Sykes, Rachel Glicksman, Selim Chaib, Paul Zamiara, Michael Milosevic, Bradly G. Wouters, Robert G. Bristow, Marianne Koritzinsky*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

215 Citations (Web of Science)

Abstract

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. 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 curativeintent, 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). 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.
Original languageEnglish
Pages (from-to)6741-6750
JournalClinical Cancer Research
Volume19
Issue number24
DOIs
Publication statusPublished - 15 Dec 2013

Cite this