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

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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 stemnessrelated 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.

Original languageEnglish
Pages (from-to)197-207
Number of pages11
JournalNeuro-Oncology
Volume19
Issue number2
DOIs
Publication statusPublished - 2017

Bibliographical note

Funding Information:
This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A2006427) and the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C0042).

All Science Journal Classification (ASJC) codes

  • Oncology
  • Clinical Neurology
  • Cancer Research

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