Altered expression of a metformin-mediated radiation response in SA-NH and FSa tumor cells treated under in vitro and in vivo growth conditions

Purpose: To assess the radiosensitizing effect of the biguanide drug metformin used alone or in combination with reactive oxygen species (ROS) modifying agents N-acetyl-L-cysteine (NAC) or emodin, and contrasted to the mitochondrial complex 1 inhibitor rotenone in altering the radiation responses of the p53 wild-type SA-NH and p53 mutant FSa mouse tumor lines grown either in vitro or in vivo. Materials and methods: Tumor cells were grown to confluence in vitro and exposed to a single 4 Gy dose in the presence or absence of metformin (5 mM) and ROS modifiers or to 10 Gy with or without metformin as tumors in the flanks of C3H mice using a tumor growth delay assay. Results: Both metformin and rotenone protected SA-NH (p <.001) while sensitizing FSa (p <.001) to 4 Gy. Neither NAC nor emodin altered metformin’s action. Metformin was also directly toxic to FSa cells (p =.002). In contrast, in vivo metformin (250 mg/kg) sensitized both SA-NH (9-day growth delay, p <.05) and FSa (4-day growth delay, p <.05) tumors if administered 1 h before irradiation. Conclusion: Metformin effects on tumor cells measured under in vitro conditions may differ from those determined in vivo due to p53 and heterogeneous environmental factors.