Glycolytic enzyme inhibitors affect pancreatic cancer survival by modulating its signaling and energetics

Anticancer Res. 2010 Mar;30(3):743-9.

Abstract

Background and aim: The importance of glycolysis in cancer cells is well documented. The effects of inhibiting glycolysis using metabolic inhibitors iodoacetate (IAA), an inhibitor of GAPDHase, and 3-bromopyruvate (3BP), an inhibitor of hexokinase-II, on survival and signaling of pancreatic cancer cells (Panc-1) were investigated.

Materials and methods: Cellular survival was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Lactate dehydrogenase (LDH) assay was used to analyze the induced necrosis and protein levels were evaluated using Western blot analysis.

Results: The results show that the inhibitors lowered cellular survival and increased cellular necrosis. Mitogenic signaling pathways were affected by 3BP but not by IAA.

Conclusion: We conclude that there may be a cross-talk between signaling pathways and glycolysis in regulating pancreatic cancer cell survival and signaling. Thus, a combination of agents that inhibit both energy production and cell signaling may provide a novel and effective approach to target pancreatic cancer effectively.

Publication types

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

MeSH terms

  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Glyceraldehyde-3-Phosphate Dehydrogenases / antagonists & inhibitors*
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism
  • Glycolysis / drug effects
  • Hexokinase / antagonists & inhibitors*
  • Hexokinase / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Iodoacetates / pharmacology*
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / enzymology*
  • Pancreatic Neoplasms / pathology
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyruvates / pharmacology*
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • ras Proteins / biosynthesis

Substances

  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Iodoacetates
  • Pyruvates
  • bromopyruvate
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Hexokinase
  • MTOR protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 3
  • ras Proteins