title: Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin.
abstract: Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS).
  
  
  
  Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model.
  
  
  
  GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness- and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS.
  
  
  
  The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM.
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Eui Hyun
authors: EH
authors: Kim
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Ji-Hyun
authors: JH
authors: Lee
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors: Yoonjee
authors: Y
authors: Oh
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors: Ilkyoo
authors: I
authors: Koh
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Jin-Kyoung
authors: JK
authors: Shim
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Junseong
authors: J
authors: Park
authors: Departments of Pharmacy, Yonsei University College of Pharmacy, Songdo, Incheon, Republic of Korea
authors: Junjeong
authors: J
authors: Choi
authors: Departments of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Mijin
authors: M
authors: Yun
authors: Departments of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Jeong Yong
authors: JY
authors: Jeon
authors: Departments of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Yong Min
authors: YM
authors: Huh
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Jong Hee
authors: JH
authors: Chang
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Sun Ho
authors: SH
authors: Kim
authors: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Kyung-Sup
authors: KS
authors: Kim
authors: Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Jae-Ho
authors: JH
authors: Cheong
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
authors: Pilnam
authors: P
authors: Kim
authors: Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors: Seok-Gu
authors: SG
authors: Kang
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000494:pharmacology*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004734:Energy Metabolism / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010085:Oxidative Phosphorylation / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000963:Antimetabolites; D007004:Hypoglycemic Agents; D008687:Metformin; D003847:Deoxyglucose
keywords: 2-deoxyglucose; glioblastoma; invasion; metformin; stemness