Reprogramming Metabolism with Metformin Improves Tumor Oxygenation and Radiotherapy Response

TLDR

Tumor hypoxia, which arises in regions far from blood vessels and contributes to radiotherapy resistance, is a negative prognostic factor in many cancers, and lowering oxygen consumption is a promising strategy to alleviate it. The study tested whether metformin, an anti‑diabetic drug that inhibits mitochondrial complex I and reduces oxygen consumption, could enhance tumor oxygenation and thereby improve radiotherapy response. Using xenograft models, the authors measured tumor oxygenation before and after metformin treatment with 2‑nitroimidazole markers, IHC, flow cytometry, and PET, and evaluated radiotherapy efficacy via tumor growth delay, clonogenic survival, and a retrospective analysis of 504 prostate cancer patients treated with IGRT. Metformin significantly increased tumor oxygenation in two xenograft models, improved radiotherapy outcomes in mice when administered pre‑irradiation, and was associated with a statistically significant reduction in early biochemical relapse rates in the clinical cohort, indicating it may be an inexpensive means to enhance radiotherapy efficacy.

Abstract

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.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.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).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.