%0 Journal Article
%T P08.66 Concomitant treatment with metformin plus temolomide increases the anti-tumor effects on glioblastoma in vitro and in vivo
%J Archive of "Neuro-Oncology".
%D 2017
%R 10.1093/neuonc/nox036.255
%X Glioblastoma (GBM) is one of the most aggressive cancers and the most common primary brain tumor. Although the concomitant chemoradiotherapy using temozolomide (TMZ) has been established as the standard therapy, the median survival is approximately 14 months. Metformin is an oral biguanide introduced in the 1950s for the treatment of type 2 diabetes. A recent epidemiologic survey found that metformin also had significant effects on tumorigenesis. The purpose of the study is to investigate the efficacy of combined therapy with TMZ and metformin for the treatment of GBM in vitro and in vivo. Metformin and TMZ inhibit survival of U87MG cells in a dose- and time-dependent manner, respectively. The combination of metformin and temzolomide enhances the antitumor effect. Flow cytometry analysis showed that combination of metformin and temzolomide induces an increase in the percentage of apoptotic cells. Notably, the combination of metformin and TMZ enhances AMPK phosphorylation and inhibit mTOR, when compared with vehicle-treated cells and single-agent therapy. In xenograft models, the survival of mice treated with combined therapy with clinically relevant dosage of TMZ and metformin is similar with that of mice treated with single-agent therapy (67 vs. 56 days). Increased dosage of metformin combined with TMZ prolongs the survival in vivo injected with U87 or TMZ-resistance U87 cells. Our results show that metformin enhances the anti-tumor effect of TMZ via AMPK-mTOR signaling pathway. The presented data reinforce that metformin might be a good candidate for combined regimen with TMZ in clinical settings
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5463949/