Metformin sensitizes hypoxia-induced geftinib treatment resistance of HNSCC via cell cycle regulation and EMT reversal

Objectives: The objectives of this study were to explore the mechanisms of metformin sensitization to hypoxia-induced geftinib treatment in resistant head and neck squamous cell carcinoma (HNSCC) and evaluate the effects of this combined treatment strategy. Methods: The effects of geftinib treatment on HNSCC were measured under normoxic and hypoxic conditions. The relationship between hypoxia and cell cycle and epithelial--mesenchymal transition (EMT) in tumor cells were analyzed. Palbociclib and LY294002 were used in combination with geftinib to evaluate the effects on HNSCC cell cytotoxicity during hypoxia. Finally, metformin was used to evaluate the sensitizing effects of geftinib treatment on HNSCC in vivo and in vitro. Results: Cell viability and apoptosis assays demonstrated a significant difference in HNSCC cells treated with geftinib between the normoxia and hypoxia groups. Hypoxia induced the expression of cyclin D1, decreased the percentage of cells in G1, and promoted the EMT of tumor cells. Both palbociclib and LY294002 enhanced geftinib-induced cytotoxicity of HNSCC cells under hypoxic conditions. Encouragingly, metformin sensitized HNSCC to geftinib treatment in vivo and in vitro. Conclusion: Hypoxia promotes G1-S cell cycle progression and EMT in HNSCC, resulting in geftinib treatment resistance. Metformin sensitizes HNSCC to geftinib treatment, which might serve as a novel combined treatment strategy. Keywords: tumor hypoxia, geftinib resistance, metformin