Role of the radiosensitizing effect of metformin added to concomitant radiotherapy with cisplatin in cervical squamous cell cancer cell lines

The radioresistance and chemoresistance may develop in cervical cancer patients during treatment. Although there are several studies reporting antiproliferative and radiosensitizing effects of metformin, the effect of metformin on the radiosensitizing effect of cisplatin when combined with chemoradiotherapy is uncertain. The aim of this study is to investigate the radiosensitizing effect of metformin per se and combined with cisplatin in human cervical cancer cell line (HeLa) and explore how radiosensitizing effect changes with activation/inhibition of AMPK. Metformin, when combined with cisplatin, did not increase the radiosensitivity of cisplatin (compared to cisplatin, p>0.05). Although the radiosensitizing effects of metformin and cisplatin per se were present in high ionizing radiation doses (both metformin and cisplatin compared to control, p<0.01), metformin did not increase the radiosensitivity of cisplatin in combination (compared to cisplatin, p>0.05). Dorsomorfin which is AMPK inhibitor potentiated cytotoxicity of cisplatin with all ionizing radiation doses, thus, dorsomorfin was found to be a more radiosensitizing agent than A769662 and metformin. Administration of A769662 24 hours prior to cisplatin treatment caused an increase in AMPK that produced resistance to cisplatin, but this effect was not observed in HeLa cells concomitantly treated with A769662 and cisplatin. The radiosensitizing effects of metformin, cisplatin, A769662, and dorsomorfin has been confirmed with analysis of DNA damage proteins, damage repair proteins and evaluation of cell cycle arrest.