Antiangiogenic activity of 2-deoxy-D-glucose

Jaime R Merchan, Krisztina Kovács, Jaclyn W. Railsback, Metin Kurtoglu, Yuqi Jing, Yolanda Piña, Ningguo Gao, Timothy G. Murray, Mark A. Lehrman, Theodore Lampidis

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Abstract

Background:During tumor angiogenesis, endothelial cells (ECS) are engaged in a number of energy consuming biological processes, such as proliferation, migration, and capillary formation. Since glucose uptake and metabolism are increased to meet this energy need, the effects of the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) on in vitro and in vivo angiogenesis were investigated. Methodology/Principal Findings:In cell culture, 2-DG inhibited EC growth, induced cytotoxicity, blocked migration, and inhibited actively forming but not established endothelial capillaries. Surprisingly, 2-DG was a better inhibitor of these EC properties than two more efficacious glycolytic inhibitors, 2-fluorodeoxy-D-glucose and oxamate. As an alternative to a glycolytic inhibitory mechanism, we considered 2-DG's ability to interfere with endothelial N-linked glycosylation. 2-DG's effects were reversed by mannose, an N-linked glycosylation precursor, and at relevant concentrations 2-DG also inhibited synthesis of the lipid linked oligosaccharide (LLO) N-glycosylation donor in a mannose-reversible manner. Inhibition of LLO synthesis activated the unfolded protein response (UPR), which resulted in induction of GADD153/CHOP and EC apoptosis (TUNEL assay). Thus, 2-DG's effects on ECS appeared primarily due to inhibition of LLOS synthesis, not glycolysis. 2-DG was then evaluated in two mouse models, inhibiting angiogenesis in both the matrigel plug assay and the LHBETATAG transgenic retinoblastoma model. Conclusions/Significance:In conclusion, 2-DG inhibits endothelial cell angiogenesis in vitro and in vivo, at concentrations below those affecting tumor cells directly, most likely by interfering with N-linked glycosylation rather than glycolysis. Our data underscore the importance of glucose metabolism on neovascularization, and demonstrate a novel approach for anti-angiogenic strategies. 2010 Merchan et al.

Original languageEnglish
Article numbere13699
JournalPLoS One
Volume5
Issue number10
DOIs
StatePublished - Nov 17 2010

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Deoxyglucose
Glycosylation
glucose
angiogenesis
Endothelial cells
glycosylation
Endothelial Cells
Glycolysis
Mannose
Metabolism
Glucose
endothelial cells
Tumors
Assays
glycolysis
mannose
Biological Phenomena
Unfolded Protein Response
oligosaccharides
synthesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Merchan, J. R., Kovács, K., Railsback, J. W., Kurtoglu, M., Jing, Y., Piña, Y., ... Lampidis, T. (2010). Antiangiogenic activity of 2-deoxy-D-glucose. PLoS One, 5(10), [e13699]. https://doi.org/10.1371/journal.pone.0013699

Antiangiogenic activity of 2-deoxy-D-glucose. / Merchan, Jaime R; Kovács, Krisztina; Railsback, Jaclyn W.; Kurtoglu, Metin; Jing, Yuqi; Piña, Yolanda; Gao, Ningguo; Murray, Timothy G.; Lehrman, Mark A.; Lampidis, Theodore.

In: PLoS One, Vol. 5, No. 10, e13699, 17.11.2010.

Research output: Contribution to journalArticle

Merchan, JR, Kovács, K, Railsback, JW, Kurtoglu, M, Jing, Y, Piña, Y, Gao, N, Murray, TG, Lehrman, MA & Lampidis, T 2010, 'Antiangiogenic activity of 2-deoxy-D-glucose', PLoS One, vol. 5, no. 10, e13699. https://doi.org/10.1371/journal.pone.0013699
Merchan JR, Kovács K, Railsback JW, Kurtoglu M, Jing Y, Piña Y et al. Antiangiogenic activity of 2-deoxy-D-glucose. PLoS One. 2010 Nov 17;5(10). e13699. https://doi.org/10.1371/journal.pone.0013699
Merchan, Jaime R ; Kovács, Krisztina ; Railsback, Jaclyn W. ; Kurtoglu, Metin ; Jing, Yuqi ; Piña, Yolanda ; Gao, Ningguo ; Murray, Timothy G. ; Lehrman, Mark A. ; Lampidis, Theodore. / Antiangiogenic activity of 2-deoxy-D-glucose. In: PLoS One. 2010 ; Vol. 5, No. 10.
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