Increasing interest in repurposing the diabetic medication
metformin for
cancer treatment has raised important questions about the translation of promising preclinical findings to therapeutic efficacy, especially in non-diabetic patients. A significant limitation of the findings to date is the use of supraphysiologic
metformin doses and hyperglycemic conditions in vitro. Our goals were to determine the impact of
hyperglycemia on
metformin response and to address the applicability of
metformin as a
cancer therapeutic in non-diabetic patients. In normoglycemic conditions, lower concentrations of
metformin were required to inhibit cell viability, while
metformin treatment in hyperglycemic conditions resulted in increased
glucose uptake and glycolytic flux, contributing to cell survival. Mechanistically, maintenance of c-Myc expression under conditions of
hyperglycemia or via gene amplification facilitated metabolic escape from the effects of
metformin. In vivo, treatment of an
ovarian cancer mouse model with
metformin resulted in greater
tumor weight reduction in normoglycemic vs. hyperglycemic mice, with increased c-Myc expression observed in
metformin-treated hyperglycemic mice. These findings indicate that
hyperglycemia inhibits the anti-
cancer effects of
metformin in vitro and in vivo. Furthermore, our results suggest that
metformin may elicit stronger responses in normoglycemic vs. hyperglycemic patients, highlighting the need for prospective clinical testing in patients without diabetes.