Metformin as a Radiation Modifier; Implications to Normal Tissue Protection and Tumor Sensitization

Abstract

Background: Nowadays, ionizing radiation is used for several applications in medicine, industry, agriculture, and nuclear power generation. Besides the beneficial roles of ionizing radiation, there are some concerns about accidental exposure to radioactive sources. The threat posed by its use in terrorism is of global concern. Furthermore, there are several side effects to normal organs for patients who had undergone radiation treatment for cancer. Hence, the modulation of radiation response in normal tissues was one of the most important aims of radiobiology. Although, so far, several agents have been investigated for protection and mitigation of radiation injury. Agents such as amifostine may lead to severe toxicity, while others may interfere with radiation therapy outcomes as a result of tumor protection. Metformin is a natural agent that is well known as an antidiabetic drug. It has shown some antioxidant effects and enhances DNA repair capacity, thereby ameliorating cell death following exposure to radiation. Moreover, through targeting endogenous ROS production within cells, it can mitigate radiation injury. This could potentially make it an effective radiation countermeasure. In contrast to other radioprotectors, metformin has shown modulatory effects through induction of several genes such as AMPK, which suppresses reduction/ oxidation (redox) reactions, protects cells from accumulation of unrepaired DNA, and attenuates initiation of inflammation as well as fibrotic pathways. Interestingly, these properties of metformin can sensitize cancer cells to radiotherapy. Conclusion: In this article, we aimed to review the interesting properties of metformin such as radioprotection, radiomitigation and radiosensitization, which could make it an interesting adjuvant for clinical radiotherapy, as well as an interesting candidate for mitigation of radiation injury after a radiation disaster.

Sitagliptin Mitigates Total Body Irradiation-Induced Hematopoietic Injury in Mice

“…IR not only induces DNA structural damage directly through the ionizing photons, but also destroys DNA structure caused by the increase of ROS [ 47 ]. The destruction of DNA structure will lead to metabolic and functional changes and eventually lead to cell damage or death.…”

“…In this study, we observed that sitagliptin significantly decreased the oxidation level in BMMNCs, HPCs, and HSCs by inhibiting the expression of NOX4. Therefore, NOX4 is a promising IR not only induces DNA structural damage directly through the ionizing photons, but also destroys DNA structure caused by the increase of ROS [47]. The destruction of DNA structure will lead to metabolic and functional changes and eventually lead to cell damage or death.…”

Metformin alters signaling induced crosstalk and homeostasis in the carcinogenesis paradigm “Epistemology of the origin of cancer”

“…The signaling and crosstalk of remodeled fibrosis by chronic inflammation and its induction of a precancerous niche (PCN) has been reviewed [81]. Metformin protects against radiation-induced pneumonitis and fibrosis [82,83] which was reported in liver cells and found to be associated with the mechanistic target of rapamycin (mTOR)/HIF-1a inhibition [84].…”

Protection from Radiation-induced Damage in Rat’s Ileum and Colon by Combined Regimens of Melatonin and Metformin: A Histopathological Study

“…Metformin, approved by the Food and Drug Administration (FDA), is mostly used as an anti-diabetic drug. It has an antioxidant effect due to its interactions with free radicals and stimulates antioxidant defense within cells [ 13 ]. Metformin has potent stimulatory effect on DNA repair mechanisms which is mediated following upregulation of AMP-activated protein kinase (AMPK) [ 14 ].…”

“…Furthermore, metformin has potent inhibitory effect on the mitochondria electron transport chain (ETC)-1. This property of metformin can help prevent continuous production of hydrogen peroxide by mitochondria that play a key role in chronic oxidative injury after exposure to radiation [ 13 ].…”