Eui Hyun Kim1, Ji-Hyun Lee1, Yoonjee Oh2, Ilkyoo Koh2, Jin-Kyoung Shim1, Junseong Park1, Junjeong Choi3, Mijin Yun4, Jeong Yong Jeon4, Yong Min Huh5, Jong Hee Chang1, Sun Ho Kim1, Kyung-Sup Kim6, Jae-Ho Cheong7, Pilnam Kim2, Seok-Gu Kang1. 1. Departments of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. 2. Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. 3. Departments of Pharmacy, Yonsei University College of Pharmacy, Songdo, Incheon, Republic of Korea 4. Departments of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. 5. Departments of Radiology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea. 6. Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea. 7. Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Abstract
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.
Background: Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various humantumors. 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.
Authors: Isaam Ben Sahra; Claire Regazzetti; Guillaume Robert; Kathiane Laurent; Yannick Le Marchand-Brustel; Patrick Auberger; Jean-François Tanti; Sophie Giorgetti-Peraldi; Frédéric Bost Journal: Cancer Res Date: 2011-05-03 Impact factor: 12.701
Authors: Roger Stupp; Monika E Hegi; Warren P Mason; Martin J van den Bent; Martin J B Taphoorn; Robert C Janzer; Samuel K Ludwin; Anouk Allgeier; Barbara Fisher; Karl Belanger; Peter Hau; Alba A Brandes; Johanna Gijtenbeek; Christine Marosi; Charles J Vecht; Karima Mokhtari; Pieter Wesseling; Salvador Villa; Elizabeth Eisenhauer; Thierry Gorlia; Michael Weller; Denis Lacombe; J Gregory Cairncross; René-Olivier Mirimanoff Journal: Lancet Oncol Date: 2009-03-09 Impact factor: 41.316
Authors: Michalina Janiszewska; Mario L Suvà; Nicolo Riggi; Riekelt H Houtkooper; Johan Auwerx; Virginie Clément-Schatlo; Ivan Radovanovic; Esther Rheinbay; Paolo Provero; Ivan Stamenkovic Journal: Genes Dev Date: 2012-08-16 Impact factor: 11.361
Authors: Teresa Y Lee; Ubaldo E Martinez-Outschoorn; Russell J Schilder; Christine H Kim; Scott D Richard; Norman G Rosenblum; Jennifer M Johnson Journal: Front Oncol Date: 2018-08-28 Impact factor: 6.244
Authors: Bryan G Harder; Mylan R Blomquist; Junwen Wang; Anthony J Kim; Graeme F Woodworth; Jeffrey A Winkles; Joseph C Loftus; Nhan L Tran Journal: Front Oncol Date: 2018-10-23 Impact factor: 6.244