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

Natalia 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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 N1-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.

Original languageEnglish (US)
Pages (from-to)172-181
Number of pages10
JournalNutrition and Cancer
Volume56
Issue number2
DOIs
StatePublished - 2006

Fingerprint

Sulindac
Adenomatous Polyposis Coli
Putrescine
anticarcinogenic activity
putrescine
animal models
Polyamines
polyamines
Adenosylmethionine Decarboxylase
adenosylmethionine decarboxylase
Spermine
spermine
spermidine
carcinogenesis
Carcinogenesis
Enzymes
Anticarcinogenic Agents
ornithine decarboxylase
Gastrointestinal Contents
acetyltransferases

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Oncology
  • Food Science

Cite this

Ignatenko, N., Besselsen, D. G., Basu Roy, U. K., Stringer, D. E., Blohm-Mangone, K. A., Padilla-Torres, J. L., ... Gerner, E. W. (2006). Dietary putrescine reduces the intestinal anticarcinogenic activity of sulindac in a murine model of familial adenomatous polyposis. Nutrition and Cancer, 56(2), 172-181. https://doi.org/10.1207/s15327914nc5602_8

Dietary putrescine reduces the intestinal anticarcinogenic activity of sulindac in a murine model of familial adenomatous polyposis. / Ignatenko, Natalia; Besselsen, David G.; Basu Roy, Upal K.; Stringer, David E.; Blohm-Mangone, Karen A.; Padilla-Torres, Jose L.; Guillen-R, Jose M.; Gerner, Eugene W.

In: Nutrition and Cancer, Vol. 56, No. 2, 2006, p. 172-181.

Research output: Contribution to journalArticle

Ignatenko, N, Besselsen, DG, Basu Roy, UK, Stringer, DE, Blohm-Mangone, KA, Padilla-Torres, JL, Guillen-R, JM & Gerner, EW 2006, 'Dietary putrescine reduces the intestinal anticarcinogenic activity of sulindac in a murine model of familial adenomatous polyposis', Nutrition and Cancer, vol. 56, no. 2, pp. 172-181. https://doi.org/10.1207/s15327914nc5602_8
Ignatenko, Natalia ; Besselsen, David G. ; Basu Roy, Upal K. ; Stringer, David E. ; Blohm-Mangone, Karen A. ; Padilla-Torres, Jose L. ; Guillen-R, Jose M. ; Gerner, Eugene W. / Dietary putrescine reduces the intestinal anticarcinogenic activity of sulindac in a murine model of familial adenomatous polyposis. In: Nutrition and Cancer. 2006 ; Vol. 56, No. 2. pp. 172-181.
@article{32474e55ee5940cf9a2c40ab1befabf0,
title = "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 N1-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.",
author = "Natalia Ignatenko and Besselsen, {David G.} and {Basu Roy}, {Upal K.} and Stringer, {David E.} and Blohm-Mangone, {Karen A.} and Padilla-Torres, {Jose L.} and Guillen-R, {Jose M.} and Gerner, {Eugene W.}",
year = "2006",
doi = "10.1207/s15327914nc5602_8",
language = "English (US)",
volume = "56",
pages = "172--181",
journal = "Nutrition and Cancer",
issn = "0163-5581",
publisher = "Routledge",
number = "2",

}

TY - JOUR

T1 - Dietary putrescine reduces the intestinal anticarcinogenic activity of sulindac in a murine model of familial adenomatous polyposis

AU - Ignatenko, Natalia

AU - Besselsen, David G.

AU - Basu Roy, Upal K.

AU - Stringer, David E.

AU - Blohm-Mangone, Karen A.

AU - Padilla-Torres, Jose L.

AU - Guillen-R, Jose M.

AU - Gerner, Eugene W.

PY - 2006

Y1 - 2006

N2 - 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 N1-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.

AB - 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 N1-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.

UR - http://www.scopus.com/inward/record.url?scp=33947215445&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33947215445&partnerID=8YFLogxK

U2 - 10.1207/s15327914nc5602_8

DO - 10.1207/s15327914nc5602_8

M3 - Article

VL - 56

SP - 172

EP - 181

JO - Nutrition and Cancer

JF - Nutrition and Cancer

SN - 0163-5581

IS - 2

ER -