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

Overview

MeSH

  • Animals
  • Cell Line, Tumor
  • Chemoprevention
  • HT29 Cells
  • Humans
  • Mice
  • Ornithine Decarboxylase Inhibitors
  • S-Adenosylmethionine

MeSH Major

  • Colorectal Neoplasms
  • Eflornithine
  • Enzyme Inhibitors
  • Thymidine

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. 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. ©2013 AACR.

publication date

  • September 2013

has subject area

  • Animals
  • Cell Line, Tumor
  • Chemoprevention
  • Colorectal Neoplasms
  • Eflornithine
  • Enzyme Inhibitors
  • HT29 Cells
  • Humans
  • Mice
  • Ornithine Decarboxylase Inhibitors
  • S-Adenosylmethionine
  • Thymidine

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3770777

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-12-0305

PubMed ID

  • 23771434

Additional Document Info

start page

  • 1072

end page

  • 1081

volume

  • 3

number

  • 9