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Metformin Topical Ointment Reduces Acute Damage in Irradiated Human Skin by Blocking TGFβ Signaling Through Modulation of AMPK and mTOR
Alexa Rivera del Rio Hernandez
*, Naresh Mahajan, Jose A. Arellano, Hamid Malekzadeh, Ethan Banks, Shawn Loder, Fuat Baris Bengur, Jeffrey Gusenoff, Francesco Egro, J.Peter Rubin, Asim Ejaz
Plastic Surgery, University of Pittsburgh, Pittsburgh, PA
INTRODUCTION: In breast cancer treatment, radiation-induced skin damage remains a significant concern. Radiation exposure can lead to radiation-induced skin fibrosis (RISF), with functional and anatomical impairments. Ionizing radiation (IR) promotes fibrosis by activating reactive oxygen species, TGF-ß and mTOR signaling pathways. Metformin targets crucial proteins involved in these pathways, downregulating the fibrotic process. We aimed to assess its capability to mitigate RISF on a human skin model.
METHODS: Using our ex vivo human skin perfusion system, a human tissue was subjected to 15 Gy of IR. The experimental interventions involved the topical application of metformin cream, control cream and no intervention. Skin biopsies were taken at set timepoints to assess histological and molecular changes.
RESULTS: Therapeutic metformin showed promising results in mitigating radiation damage to epithelial cells. Histology in the metformin-treated group consistently showed reduced cell damage, fibrosis, and epidermal-dermal disruption, when compared to the non-treated groups. In the metformin-treated group, TUNEL demonstrated the lowest percentage of cell death and γ-H2AX showcased lessened DNA damage. We also observed increased elastogenesis in this group. Metformin treated skin showed higher expression of ECM remodeling, antioxidant, DNA repair and antiapoptotic gene expression, with attenuation of proinflammatory markers. Reduced activity of mTOR and TGF-ß1, and increased activity of AMPK showcased metformin's capability to downregulate pro-fibrotic pathways.
CONCLUSION: Results demonstrated that metformin downregulates proteins involved in fibroblast activation pathways, helping maintain skin's structural integrity and enhancing cellular resilience under stress, after radiation injury. It also promotes DNA repair and protects against DNA damage. Our findings showcase metformin as a promising therapeutic agent to mitigate RISF, with clinical implications for preventing cutaneous functional and anatomical impairments in patients receiving radiation therapy.
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