Korean J Otorhinolaryngol-Head Neck Surg.  2024 Sep;67(9):488-495. 10.3342/kjorl-hns.2024.00038.

Synergistic Inhibition of Head and Neck Cancer Cell Proliferation by Combined Metformin and Radiotherapy Treatment

• Yeo J
• Lee DH
• Bae AY
• Moon DH
• Bang J
• Kim JS
• Park JO

• KMID: 2559347
• DOI: http://doi.org/10.3342/kjorl-hns.2024.00038

Abstract

Background and Objectives
Metformin, a commonly used antidiabetic drug, has been reported to exhibit promising anticancer effects across various tumor types. This study investigated the effectiveness of combining metformin with radiotherapy (RT) to treat head and neck squamous cell carcinoma (HNSCC). Materials and Method In vitro experiments were conducted in which FaDu and SCC-25 cells were treated with metformin, followed by irradiation. Cell proliferation was evaluated by MTT assay, and apoptosis was assessed by staining with annexin V-fluorescein isothiocyanate/ propidium iodide, followed by flow cytometry. Western blotting was performed to evaluate changes in apoptotic markers. In vivo experiments were performed using a murine AT-84 allograft model, where tumor volume was measured and serum samples were collected to assess the level of vascular endothelial growth factor (VEGF).
Results
The combination of metformin and RT significantly reduced cell proliferation in a dose- and time-dependent manner, and led to a significant increase in the apoptotic rate, accompanied by the upregulation of cleaved caspase-8 and FoxO3, and the downregulation of Bcl-2. The combination treatment also exhibited antiangiogenic effects, as shown by the reduced hypoxia-inducible factor-1 alpha level and inhibited tube formation in the endothelial cells. The combined therapy in the mouse model led to marked decrease in tumor volume and the serum VEGF level in comparison to both the control group and the RT alone.
Conclusion
The concurrent use of metformin and RT successfully suppressed cell proliferation, triggered apoptosis, and increased the antiangiogenic effects in HNSCC. These results support the use of metformin as an adjunct to RT for the treatment of HNSCC.

Keyword

Apoptosis; Drug therapy, combination; Head and neck squamous cell carcinoma; Metformin; Radiotherapy