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

• Published in: Cancer discovery 2013-06, Vol.3 (9), p.1072-1081
• Main Authors: Witherspoon, Mavee, Chen, Qiuying, Kopelovich, Levy, Gross, Steven S., Lipkin, Steven
• Format: Article
• Language: English
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-12-0305

The ornithine decarboxylase (ODC) inhibitor, α-difluoromethylornithine (DFMO), is a highly effective chemopreventative agent for colorectal cancer (CRC) thought to act via polyamine depletion. However, in DFMO treated patients, mucosal polyamine levels do not directly correlate with CRC risk. Untargeted metabolite profiling was used to broadly survey DFMO actions on colon cancer cell metabolism. Some studies revealed that DFMO treatment of ApcMin intestinal tumors and human CRC 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 (THF) from thymidylate synthase and thereby diminishing 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.