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

ABSTRACT:

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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 tetrahydrofo

SUBMITTER: Witherspoon M 

PROVIDER: S-EPMC3770777 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature