Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation

Mol Cancer Ther. 2007 Nov;6(11):3049-58. doi: 10.1158/1535-7163.MCT-07-0310.


In tumor cells growing under hypoxia, inhibiting glycolysis with 2-deoxy-d-glucose (2-DG) leads to cell death, whereas under normoxic conditions cells similarly treated survive. Surprisingly, here we find that 2-DG is toxic in select tumor cell lines growing under normal oxygen tension. In contrast, a more potent glycolytic inhibitor, 2-fluorodeoxy-d-glucose, shows little or no toxicity in these cell types, indicating that a mechanism other than inhibition of glycolysis is responsible for their sensitivity to 2-DG under normoxia. A clue to this other mechanism comes from previous studies in which it was shown that 2-DG interferes with viral N-linked glycosylation and is reversible by exogenous addition of mannose. Similarly, we find that 2-DG interferes with N-linked glycosylation more potently in the tumor cell types that are sensitive to 2-DG under normoxia, which can be reversed by exogenous mannose. Additionally, 2-DG induces an unfolded protein response, including up-regulation of GADD153 (C/EBP-homologous protein), an unfolded protein response-specific mediator of apoptosis, more effectively in 2-DG-sensitive cells. We conclude that 2-DG seems to be toxic in select tumor cell types growing under normoxia by inhibition of N-linked glycosylation and not by glycolysis. Because in a phase I study 2-DG is used in combination with an anticancer agent to target hypoxic cells, our results raise the possibility that in certain cases, 2-DG could be used as a single agent to selectively kill both the aerobic (via interference with glycosylation) and hypoxic (via inhibition of glycolysis) cells of a solid tumor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Aerobiosis / drug effects
  • Anaerobiosis / drug effects
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Deoxyglucose / pharmacology*
  • Fluorodeoxyglucose F18 / pharmacology
  • Glycolysis / drug effects*
  • Glycosylation / drug effects
  • Humans
  • Mannose / pharmacology
  • Models, Biological
  • Neoplasms / pathology*
  • Oligosaccharides / metabolism
  • Oxygen / metabolism*
  • Oxygen Consumption / drug effects
  • Protein Folding
  • Transcription Factor CHOP / genetics
  • Up-Regulation / drug effects


  • Oligosaccharides
  • Fluorodeoxyglucose F18
  • Transcription Factor CHOP
  • Adenosine Triphosphate
  • Deoxyglucose
  • Mannose
  • Oxygen