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Metformin topical ointment reduce acute damage in irradiated human skin by blocking TGFβ signaling through modulation of AMPK and mTOR signaling
Alexa Rivera del Rio Hernandez, MD ; Naresh Mahajan, PhD; Jose Antonio Arellano, MD; Hamid Malekzadeh, MD; Yusuf Surucu, MD; Fuat Baris Bengur, MD; Shawn Loder, MD; James H-C Wang, PhD; Juan J. Andrade-Rojas, MD; Jeffrey A. Gusenoff, MD; Francesco M. Egro, MBChB, MSc, MRCS; J. Peter Rubin, MD, FACS, MBA; Asim Ejaz, PhD
University of Pittsburgh
2024-12-11
Presenter: Alexa Rivera del Rio Hernandez, MD
Affidavit:
I certify that the material proposed for presentation in this abstract has not been published in any scientific journal or previously presented at a major meeting.
Director Name: J. Peter Rubin
Author Category: Fellow Plastic Surgery
Presentation Category: Basic Science Research
Abstract Category: General Reconstruction
INTRODUCTION: Radiation therapy is crucial in modern cancer treatment, however, radiation-induced skin damage remains a significant concern. Radiation-induced skin fibrosis (RISF), leads to functional and anatomical impairments. Ionizing radiation promotes fibrosis through reactive oxygen species (ROS) production, metabolic reprogramming and DNA damage. Metformin holds promise in mitigating fibrosis by targeting key proteins involved in these pathways. Our previous research has demonstrated intraperitoneal metformin's effects in reducing skin fibrosis in mice. We have developed a proprietary metformin lotion to assess its ability to mitigate acute phase radiation damage in a human skin model.
METHODS: Utilizing our innovative ex vivo human skin perfusion system, human tissue was subjected to radiation-induced damage at a dosage of 15 Gy. Treatments included metformin topical cream, control cream and no intervention. Biopsies were scheduled for histological and molecular analysis.
RESULTS: Metformin-treated skin showed reduced cell damage, fibrosis, and epidermal-dermal disruption. TUNEL and γ-H2AX results showcased decreased cell death and DNA damage. Gene expression analysis exhibited higher levels of ECM remodeling, antioxidant, DNA repair, cellular proliferation and antiapoptotic markers, with reduced proinflammatory markers. Pro-fibrotic pathways (mTOR, p70S6K and TGF-B) were diminished, while AMPK activity increased in metformin-treated skin.
CONCLUSION: Metformin decreases the activity of proteins involved in the pathways that drive fibroblast activation. After radiation injury, metformin supports structural integrity of skin, protects DNA, enhances cellular resilience and reduces fibrotic activity. These findings make metformin a promising therapeutic agent for managing radiation-induced skin damage and preventing functional and anatomical impairments in patients receiving radiation therapy.
