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A novel biguanide (IM1761065) inhibits bioenergetics of glioblastoma tumorspheres

Authors
 Tae Hoon Roh  ;  Ji-Hyun Lee  ;  Seo Jin Kim  ;  Jin-Kyoung Shim  ;  Junseong Park  ;  Seon-Jin Yoon  ;  Wan-Yee Teo  ;  Se Hoon Kim  ;  Jong Hee Chang  ;  Seok-Gu Kang 
Citation
 JOURNAL OF NEURO-ONCOLOGY, Vol.156(1) : 139-151, 2022-01 
Journal Title
JOURNAL OF NEURO-ONCOLOGY
ISSN
 0167-594X 
Issue Date
2022-01
Keywords
Biguanide ; Bioenergetics ; Glioblastoma ; IM1761065 ; Tumorsphere
Abstract
Purpose: Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs).

Methods: The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model.

Results: IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (P = 0.0289, log-rank test).

Conclusion: IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM.
Full Text
https://link.springer.com/article/10.1007/s11060-021-03903-7
DOI
10.1007/s11060-021-03903-7
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187855
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