title: Metformin inhibits growth of human glioblastoma cells and enhances therapeutic response.
abstract: 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.
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
authors: Julie
authors: J
authors: Sesen
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
authors: Perrine
authors: P
authors: Dahan
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France; Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors: Sarah J
authors: SJ
authors: Scotland
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
authors: Estelle
authors: E
authors: Saland
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
authors: Van-Thi
authors: VT
authors: Dang
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
authors: Anthony
authors: A
authors: Lemarié
authors: Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors: Betty M
authors: BM
authors: Tyler
authors: Department of Neurosurgery, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors: Henry
authors: H
authors: Brem
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
authors: Christine
authors: C
authors: Toulas
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
authors: Elizabeth
authors: E
authors: Cohen-Jonathan Moyal
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
authors: Jean-Emmanuel
authors: JE
authors: Sarry
authors: INSERM U1037, Centre de Recherche en Cancérologie de Toulouse, Toulouse, France.
authors: Nicolas
authors: N
authors: Skuli
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001932:Brain Neoplasms / Q000473:pathology* / Q000532:radiotherapy; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005909:Glioblastoma / Q000473:pathology* / Q000532:radiotherapy; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D000077204:Temozolomide; D014157:Transcription Factors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C469991:DDIT4 protein, human; D014157:Transcription Factors; D003606:Dacarbazine; D008687:Metformin; D000263:Adenylate Kinase; D000077204:Temozolomide