Augmented Pentose Phosphate Pathway Plays Critical Roles in Colorectal Carcinomas

Oncology. 2015;88(5):309-19. doi: 10.1159/000369905. Epub 2015 Jan 14.

Abstract

Glycolysis and the pentose phosphate pathway (PPP) are preferentially activated in cancer cells. Accumulating evidence indicated the significance of the altered glucose metabolism in cancer, but the implication for oncotherapy remains unclear. Here we report that the synthesis of glycolytic and PPP enzymes is almost ubiquitously augmented in colorectal carcinoma (CRC) specimens. The mammalian target of rapamycin (mTOR) inhibitor INK128 (300 nM) and phytochemical Avemar (1 mg/ml) inhibited the synthesis of PPP enzymes in CRC cell lines. INK128 (150-600 nM) and resveratrol (75-300 μM) inhibited aerobic glycolysis in the cell lines. INK128 (300 nM) and Avemar (1 mg/ml) decreased the NADPH/NADP(+) ratio as well as the GSH/GSSG ratio in the cell lines. Finally, per os administration of INK128 (0.8 mg/kg) or Avemar (1 g/kg) suppressed tumor growth and delayed tumor formation by transplantable CRC specimens derived from patients. Taken together, pharmacological inhibition of the mTOR-PPP axis is a promising therapeutic strategy against CRCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Benzoxazoles / administration & dosage
  • Benzoxazoles / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / metabolism*
  • Female
  • Glucose / metabolism
  • Glutathione Disulfide / metabolism
  • Glycolysis / drug effects
  • Humans
  • Japan
  • Lactic Acid / metabolism
  • Mice
  • Mice, Nude
  • Pentose Phosphate Pathway / drug effects*
  • Plant Extracts / administration & dosage
  • Plant Extracts / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*
  • Receptors, Peptide / metabolism
  • Resveratrol
  • Stilbenes / administration & dosage
  • Stilbenes / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • Transplantation, Heterologous
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Avemar
  • Benzoxazoles
  • INK128
  • Plant Extracts
  • Pyrimidines
  • Receptors, Peptide
  • Stilbenes
  • glutathione receptor
  • Lactic Acid
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Glucose
  • Resveratrol
  • Glutathione Disulfide