Metformin May Play a Surprising Role in Radiation Protection

High doses of radiation pose significant risks to the human body, particularly for patients with cancer undergoing treatment or astronauts exposed to intense radiation from the Sun. For this reason, improving radioprotection for these populations is crucial. A study, led by Dr. Silvia Siteni at the University of Texas Southwestern Medical Center and published in PLOS One, demonstrates the role that metformin could play in radioprotection for these at-risk groups.

The potential of metformin

Metformin is a medication currently used for treating diabetes mellitus type 2 and has been prescribed to over 150 million patients worldwide, proving particularly useful because of its ability to reduce hyperglycemia without causing hypoglycemia or weight gain. Although its mechanism of action is still not well understood, it is known to have antioxidant effects through mitochondrial targeting and activation of adenosine monophosphate-activated protein kinase (AMPK). Recent research suggests metformin may also have potential as a radioprotector, as evidenced by its ability to protect human cells from radiation-induced DNA damage and oxidative stress.

In vitro and in vivo mechanisms of metformin’s activity

The researchers first performed a CellTiter-Glo (CTG) analysis to understand the short-term effects of metformin on human BJ fibroblasts. From this, they conducted a clonogenic assay to evaluate the long-term survival of these cells after treatment with various metformin concentrations. Next, they wanted to investigate the activation of AMPK and the role of superoxide dismutase (SOD1) in the radioprotective pathway, so they treated cells with 0.5 mM metformin and analyzed protein expression via western blot. They also irradiated the BJ fibroblasts with gamma rays after metformin treatment and assessed DNA damage via Comet assays and γH2AX foci. In vivo studies were conducted where they treated mice with metformin and then exposed them to ionizing radiation or simulated galactic cosmic radiation, and then assessed DNA damage and survival afterwards.

The key findings from this study were that:

• 0.5 mM metformin significantly increased the expression of SOD1 and phosphorylated AMPK in BJ fibroblasts
• Higher doses of metformin reduced cell survival
• Treatment with metformin significantly reduced DNA damage in irradiated BJ fibroblasts
• Metformin treatment reduced the number of micronuclei in bone marrow cells of the mice and decreased DNA damage in their colon and lung tissues
• Metformin improved survival of mice who were exposed to ionizing radiation, specifically with 37% of treated mice surviving compared to 0% of untreated mice

Metformin as a pre-treatment for radiation exposure

Metformin was able to increase the expression of SOD1 and phosphorylated AMPK, both of which indicate the activation of detoxification pathways, which is desirable in people who are exposed to high levels of radiation. Furthermore, treatment with metformin reduced DNA damage in fibroblasts, also indicating its protective effect against radiation. The in vivo studies are also promising, in that metformin reduced the number of micronuclei in bone marrow cells, which are indicators of DNA damage or genomic instability. Additionally, the treatment improved overall survival in mice, suggesting overarching improvement in health.

High doses of radiation are capable of causing significant DNA damage and the results of this study led by Dr. Siteni show that metformin has promise as a pre-treatment for people exposed to intense concentrations of radiation, such as cancer patients and astronauts. However, further experimentation is required before this research is considered for clinical trials. Firstly, dose optimization is crucial, as high concentrations of metformin reduced overall cell survival in this study. In order for metformin to be safe to administer for radioprotection, the current dosage that maximizes efficacy and safety is important. Furthermore, although AMPK and SOD1 activation were linked to metformin’s protective effects, the specific molecular mechanisms behind DNA repair and reduced oxidative stress still needs further understanding. Thinking into the future, if metformin were to be administered to humans on a regular basis for radioprotection over the course of cancer treatment, it’s crucial to also conduct long-term studies in vivo to understand its impact over a longer period of time.

Next steps before clinical trials

This study shows promise in using metformin for radioprotection. This could be particularly useful for patients with cancer who receive frequent doses of radiation or astronauts who spend a lot of time exposed to dangerous levels of radiation through explosions on the solar surface and galactic cosmic radiation. However, before stepping into clinical trials, scientists must determine the most effective dose for radioprotection and better understand the long-term impacts of the drug when used at that level.

Reference: Siteni S, Barron S, Luitel K, Shay JW. Radioprotective effect of the anti-diabetic drug metformin. PLoS One. 2024;19(7):e0307598. doi:10.1371/journal.pone.0307598

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