High-grade
gliomas,
glioblastomas (GB), are refractory to conventional treatment combining surgery,
chemotherapy, mainly
temozolomide, and
radiotherapy. This highlights an urgent need to develop novel
therapies and increase the efficacy of radio/
chemotherapy for these very aggressive and malignant
brain tumors. Recently,
tumor metabolism became an interesting potential therapeutic target in various
cancers. Accordingly, combining drugs targeting cell metabolism with appropriate chemotherapeutic agents or
radiotherapy has become attractive. In light of these perspectives, we were particularly interested in the anti-
cancer properties of a
biguanide molecule used for
type 2 diabetes treatment,
metformin. In our present work, we demonstrate that
metformin decreases mitochondrial-dependent
ATP production and oxygen consumption and increases
lactate and glycolytic
ATP production. We show that
metformin induces decreased proliferation, cell cycle arrest, autophagy, apoptosis and cell death in vitro with a concomitant activation of AMPK, Redd1 and inhibition of the mTOR pathway. Cell sensitivity to
metformin also depends on the genetic and mutational backgrounds of the different GB cells used in this study, particularly their PTEN status. Interestingly, knockdown of AMPK and Redd1 with
siRNA partially, but incompletely, abrogates the induction of apoptosis by
metformin suggesting both AMPK/Redd1-dependent and -independent effects. However, the primary determinant of the effect of
metformin on cell growth is the genetic and mutational backgrounds of the
glioma cells. We further demonstrate that
metformin treatment in combination with
temozolomide and/or irradiation induces a synergistic anti-tumoral response in
glioma cell lines. Xenografts performed in nude mice demonstrate in vivo that
metformin delays
tumor growth. As current treatments for GB commonly fail to cure, the need for more effective therapeutic options is overwhelming. Based on these results,
metformin could represent a potential enhancer of the cytotoxic effects of
temozolomide and/or
radiotherapy.