Unbiased metabolite profiling indicates that a diminished thymidine pool is the underlying mechanism of colon cancer chemoprevention by alpha-difluoromethylornithine

Cancer Discov. 2013 Sep;3(9):1072-81. doi: 10.1158/2159-8290.CD-12-0305. Epub 2013 Jun 14.

Abstract

The ornithine decarboxylase inhibitor α-difluoromethylornithine (DFMO) is a highly effective chemopreventive agent for colorectal cancer thought to act via polyamine depletion. However, in DFMO-treated patients, mucosal polyamine levels do not directly correlate with colorectal cancer risk. Untargeted metabolite profiling was used to broadly survey DFMO actions on colon cancer cell metabolism. We found that DFMO treatment of Apc(Min) intestinal tumors and human colorectal cancer cells is associated with reduced levels of folate-dependent metabolites, including S-adenosylmethionine (SAM), thymidine pools, and related pathway intermediates. We hypothesized that unrestrained SAM consumption/regeneration constitutes a futile DFMO-triggered cascade that can steal tetrahydrofolate from thymidylate synthase and thereby diminish thymidine pools. In accord with this hypothesis, DFMO treatment altered the folate cofactor balance and thymidine supplementation prevented DFMO-elicited cytostasis without restoring polyamine levels. These findings suggest that thymidine metabolite pool insufficiency is a fundamental mechanism of DFMO cytostatic activity.

Significance: A previously unappreciated metabolic linkage between polyamine and thymidine biosynthesis is revealed, based on the competing requirement of these pathways for a limited pool of tetrahydrofolate cofactor. This study identifies the fi rst shared mechanism for colorectal cancer chemoprevention and chemotherapy, suggesting a common metabolic target for both premalignant and malignant colon cells.

Publication types

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

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chemoprevention
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / prevention & control
  • Eflornithine / pharmacology*
  • Enzyme Inhibitors / pharmacology*
  • HT29 Cells
  • Humans
  • Mice
  • Ornithine Decarboxylase Inhibitors
  • S-Adenosylmethionine / metabolism
  • Thymidine / metabolism*
  • Thymidine / pharmacology*

Substances

  • Enzyme Inhibitors
  • Ornithine Decarboxylase Inhibitors
  • S-Adenosylmethionine
  • Thymidine
  • Eflornithine