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Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin

 Eui Hyun Kim  ;  Ji-Hyun Lee  ;  Yoonjee Oh  ;  Ilkyoo Koh  ;  Jin-Kyoung Shim  ;  Junseong Park  ;  Junjeong Choi  ;  Mijin Yun  ;  Jeong Yong Jeon  ;  Yong Min Huh  ;  Jong Hee Chang  ;  Sun Ho Kim  ;  Kyung-Sup Kim  ;  Jae-Ho Cheong  ;  Pilnam Kim  ;  Seok-Gu Kang 
 NEURO-ONCOLOGY, Vol.19(2) : 197-207, 2017 
Journal Title
Issue Date
Animals ; Antimetabolites/pharmacology ; Apoptosis/drug effects ; Brain Neoplasms/drug therapy* ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Cell Proliferation/drug effects ; Deoxyglucose/pharmacology* ; Drug Synergism ; Drug Therapy, Combination ; Energy Metabolism/drug effects ; Glioblastoma/drug therapy* ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Glycolysis/drug effects ; Humans ; Hypoglycemic Agents/pharmacology ; Metformin/pharmacology* ; Mice ; Mice, Nude ; Oxidative Phosphorylation/drug effects ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
2-deoxyglucose ; glioblastoma ; invasion ; metformin ; stemness
BACKGROUND: 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).

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kim, Kyung Sup(김경섭) ORCID logo https://orcid.org/0000-0001-8483-8537
Kim, Sun Ho(김선호) ORCID logo https://orcid.org/0000-0003-0970-3848
Kim, Eui Hyun(김의현) ORCID logo https://orcid.org/0000-0002-2523-7122
Yun, Mi Jin(윤미진) ORCID logo https://orcid.org/0000-0002-1712-163X
Lee, Ji Hyun(이지현) ORCID logo https://orcid.org/0000-0002-9223-9478
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
Jeon, Jeong Yong(전정용)
Cheong, Jae Ho(정재호) ORCID logo https://orcid.org/0000-0002-1703-1781
Huh, Yong Min(허용민) ORCID logo https://orcid.org/0000-0002-9831-4475
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