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Assessment Of Prophylactic And Therapeutic Efficacy Of Metformin And Adipose Stem Cells In A Mice Radiation-induced Skin Fibrosis
Hamid Malekzadeh, MD, Yusuf Surucu, MD, Somaiah Chinnapaka, PhD, Katherine S. Yang, BS, José Arellano, MD, Michael Epperly, MD, FACRO, Joel Greenberger, MD, FACRO, J. Peter Rubin, MD, FACS, MBA, Asim Ejaz, PhD;
University of Pittsburgh, pittsburgh, PA, USA
Purpose: Half of all cancer patients undergo radiation therapy as part of their treatment regimen, often resulting in late radiation-induced skin fibrosis (RIF). Management typically involves physical therapy, steroids, and fat grafting, yet they usually offer limited scope and efficacy. In this study, we demonstrate the efficacy of metformin, adipose stem cells (ASCs), both autologous and allogeneic, and their combined therapy's potential to improve RIF.
Methods: We used C57BL/6 mice irradiated with 40 Gy to establish a hind limb skin fibrosis model. We assessed metformin (100 mg/kg, intraperitoneal), subcutaneously injected ASCs, and their combination as mitigators. We tested both prophylactic (initiated post-irradiation on day 1) and therapeutic (starting on day 14) approaches, measuring limb excursion, histological changes via Masson's Trichrome staining, and quantified inflammatory and profibrotic genes expressions.
Results: At the end of the 6-week period, metformin and ASCs demonstrated improved range of motion and histologic scores for inflammation and fibrosis (p<0.01). However, combining them did not show synergistic benefits in this context (p>0.05). In the therapeutic cohort, autologous ASCs, alone or with metformin, improved outcomes. Moreover, prophylactic treatment outperformed late-onset therapy in mitigating radiation-induced skin damage. Analyzing gene expression in transwell co-cultures revealed that ASCs and metformin, alone or combined, downregulated inflammatory and profibrotic gene expression in both mouse and human fibroblasts (p<0.001).
Conclusion: Our study highlights metformin's efficacy as a prophylactic measure against RISF. Furthermore, both autologous and allogeneic ASCs demonstrate substantial potential for prophylactic and therapeutic RIF treatment. These findings underscore the clinical significance of our research in alleviating RIF.
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