Antidiabetic biguanides are potent hypoxic radiosensitizers through targeting of mitochondrial respiration and re-oxygenation of tumor cells

Background and purpose: The anti-diabetic biguanide drugs metformin and phenformin exhibit antitumor activity in various models. However, their radiomodulatory effect under hypoxic conditions, particularly for phenformin, is largely unknown. This study therefore examines whether metformin and phenformin as mitochondrial complex I blockades could overcome hypoxic radioresistance through inhibition of oxygen consumption.

Material and methods: The radiosensitizing effect of metformin and phenformin in a panel of colorectal cancer cells was examined in vitro and further validated in vivo.

Results: Metformin and phenformin inhibited mitochondrial complex I activity and subsequently reduced oxygen consumption rate in a dose-dependent manner starting at 3mM and 30μM respectively. As a result, the hypoxic radioresistance of tumor cells was counteracted by metformin and phenformin with an enhancement ratio about 2 at 9mM and 100μM. In tumor-bearing mice, metformin or phenformin alone did not show any anti-tumor effect. While in combination with radiation, both of them substantially delayed tumor growth and enhanced radioresponse respectively by 1.3 and 1.5 folds.

Conclusions: Our results demonstrate that metformin and phenformin overcome hypoxic radioresistance through inhibition of mitochondrial respiration, and provide a rationale to explore metformin and phenformin as hypoxic radiosensitizers.