Dietary putrescine reduces the intestinal anticarcinogenic activity of sulindac in a murine model of familial adenomatous polyposis.

Abstract

The nonsteroidal antiinflammatory drug sulindac displays chemopreventive activity in patients with familial adenomatous polyposis (FAP). Sulindac metabolites induce apoptosis in colon tumor cells, in part, by a polyamine-dependent mechanism that can be suppressed with exogenous putrescine. To determine the relevance of this mechanism in animals, we treated Apc(Min/+) mice, a model of human FAP, with sulindac alone or in combination with dietary putrescine. Sulindac increased steady-state RNA levels and enzymatic activity of the polyamine catabolic enzyme spermidine/spermine N(1)-acetyltransferase and intestinal levels of monoacetylspermidine, spermidine, and spermine in the small intestine of mice. Sulindac also decreased the activity of the biosynthetic enzyme ornithine decarboxylase but not adenosylmethionine decarboxylase (AMD). Dietary putrescine increased intestinal putrescine contents, whereas the combination of dietary putrescine and sulindac yielded the highest levels of intestinal putrescine and correlated with a statistically significant reduction in AMD enzyme activity. Dietary putrescine did not statistically significantly increase tumorigenesis, although it significantly increased the grade of adenoma dysplasia (P < 0.05). The effectiveness of sulindac to suppress intestinal carcinogenesis was partially abrogated by dietary putrescine. These data suggest that sulindac exerts at least some of its anticarcinogenic effects in mice via a polyamine-dependent mechanism. Because high concentrations of putrescine can be found in certain dietary components, it may be advantageous to restrict dietary putrescine consumption in patients undergoing treatment with sulindac.

• Authors: Natalia A Ignatenko, David G Besselsen, Upal K Basu Roy, David E Stringer, Karen A Blohm-Mangone, Jose L Padilla-Torres, Jose M Guillen-R, Eugene W Gerner
• Journal: Nutrition and cancer (Nutr Cancer) Vol. 56 Issue 2 Pg. 172-81 ( 2006) ISSN: 0163-5581 [Print] United States
• PMID: 17474863 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyclooxygenase Inhibitors
• Ornithine Decarboxylase Inhibitors
• Polyamines
• RNA, Messenger
• Sulindac
• Spermine
• Ornithine Decarboxylase
• Adenosylmethionine Decarboxylase
• Spermidine
• Putrescine

Topics

• Adenomatous Polyposis Coli (drug therapy, metabolism)
• Adenosylmethionine Decarboxylase (metabolism)
• Animals
• Antineoplastic Agents (antagonists & inhibitors, therapeutic use)
• Cyclooxygenase Inhibitors (therapeutic use)
• Diet
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Interactions
• Female
• Intestine, Small (enzymology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Ornithine Decarboxylase (metabolism)
• Ornithine Decarboxylase Inhibitors
• Polyamines (metabolism)
• Putrescine (administration & dosage, pharmacology)
• RNA, Messenger (biosynthesis)
• Random Allocation
• Spermidine (metabolism)
• Spermine (metabolism)
• Sulindac (antagonists & inhibitors, therapeutic use)