Abstract
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.
Disclosure statement
Dr David J. Grdina and Dr Jeffrey S. Murley are minority equity partners in Pinnacle Oncology LLC regarding the potential novel uses of amifostine. Dr Richard C. Miller, Ms Raziye Rana Senlik and Dr Alfred W. Rademaker have no conflicts of interest to disclose. The authors alone are responsible for the content and writing of the paper.