Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations

Osamu Itano, Kan Yang, Kunhua Fan, Naoto Kurihara, Hiroharu Shinozaki, Sadanori Abe, Bo Jin, Claudia Gravaghi, Winfried Edelmann, Leonard H. Augenlicht, Levy Kopelovich, Raju Kucherlapati, Sergio Lamprecht, Martin Lipkin

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

We have previously reported that sulindac, a non-steroidal anti-inflammatory drug, inhibited tumor formation in the small intestine but increased tumors in the colon of ApcMin/+ mice, a model of human familial adenomatous polyposis. To further explore intestinal regional responses, we studied effects of sulindac on additional gene-targeted mouse models of human intestinal tumorigenesis; these were (i) Apc1638N/ mouse (chain termination mutation in exon 15 of the Apc gene); (ii) Mlh1+/- mouse (DNA mismatch repair deficiency, a mouse model of human hereditary non-polyposis colorectal cancer) and (iii) double-heterozygous Mlh1+/- Apc1638N/+ mutant mouse. Mice were fed AIN-76A control diet with or without 0.02% sulindac for 6 months. Intestinal regional tumor incidence, multiplicity, volume and degree of inflammation were used as end points. The results showed the following: (i) sulindac inhibited tumor development in the small intestine of Apc638N/+ mice; (ii) in contrast, sulindac increased tumors in the small intestine of Mlh1 mutant mice, a neoplastic effect which persisted in heterozygous compound Mlh1+/- Apc1638N/+ mutant mice; (iii) sulindac increased tumors in the cecum of all mice regardless of genetic background; (iv) sulindac decreased inflammation in the small intestine of Apc1638N/+ mice, but it increased inflammation in the small intestine of Mlh1+/- mice and Mlh1+/- Apc1638N/+ mice and (v) sulindac enhanced inflammation in the cecum of all mutant mice. Findings indicate that the effects of sulindac in the intestine of these mutant mouse models are probably related to genetic background and appear to be associated with its inflammatory-inducing response.

Original languageEnglish (US)
Pages (from-to)1923-1926
Number of pages4
JournalCarcinogenesis
Volume30
Issue number11
DOIs
StatePublished - 2009

Fingerprint

Sulindac
Intestines
Carcinogenesis
Inflammation
Mutation
Small Intestine
Neoplasms
Cecum
DNA Repair-Deficiency Disorders
Adenomatous Polyposis Coli
DNA Mismatch Repair

ASJC Scopus subject areas

  • Cancer Research

Cite this

Itano, O., Yang, K., Fan, K., Kurihara, N., Shinozaki, H., Abe, S., ... Lipkin, M. (2009). Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations. Carcinogenesis, 30(11), 1923-1926. https://doi.org/10.1093/carcin/bgp200

Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations. / Itano, Osamu; Yang, Kan; Fan, Kunhua; Kurihara, Naoto; Shinozaki, Hiroharu; Abe, Sadanori; Jin, Bo; Gravaghi, Claudia; Edelmann, Winfried; Augenlicht, Leonard H.; Kopelovich, Levy; Kucherlapati, Raju; Lamprecht, Sergio; Lipkin, Martin.

In: Carcinogenesis, Vol. 30, No. 11, 2009, p. 1923-1926.

Research output: Contribution to journalArticle

Itano, O, Yang, K, Fan, K, Kurihara, N, Shinozaki, H, Abe, S, Jin, B, Gravaghi, C, Edelmann, W, Augenlicht, LH, Kopelovich, L, Kucherlapati, R, Lamprecht, S & Lipkin, M 2009, 'Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations', Carcinogenesis, vol. 30, no. 11, pp. 1923-1926. https://doi.org/10.1093/carcin/bgp200
Itano, Osamu ; Yang, Kan ; Fan, Kunhua ; Kurihara, Naoto ; Shinozaki, Hiroharu ; Abe, Sadanori ; Jin, Bo ; Gravaghi, Claudia ; Edelmann, Winfried ; Augenlicht, Leonard H. ; Kopelovich, Levy ; Kucherlapati, Raju ; Lamprecht, Sergio ; Lipkin, Martin. / Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations. In: Carcinogenesis. 2009 ; Vol. 30, No. 11. pp. 1923-1926.
@article{8c64ec1529ba432aa7fb0842e06964f9,
title = "Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations",
abstract = "We have previously reported that sulindac, a non-steroidal anti-inflammatory drug, inhibited tumor formation in the small intestine but increased tumors in the colon of ApcMin/+ mice, a model of human familial adenomatous polyposis. To further explore intestinal regional responses, we studied effects of sulindac on additional gene-targeted mouse models of human intestinal tumorigenesis; these were (i) Apc1638N/ mouse (chain termination mutation in exon 15 of the Apc gene); (ii) Mlh1+/- mouse (DNA mismatch repair deficiency, a mouse model of human hereditary non-polyposis colorectal cancer) and (iii) double-heterozygous Mlh1+/- Apc1638N/+ mutant mouse. Mice were fed AIN-76A control diet with or without 0.02{\%} sulindac for 6 months. Intestinal regional tumor incidence, multiplicity, volume and degree of inflammation were used as end points. The results showed the following: (i) sulindac inhibited tumor development in the small intestine of Apc638N/+ mice; (ii) in contrast, sulindac increased tumors in the small intestine of Mlh1 mutant mice, a neoplastic effect which persisted in heterozygous compound Mlh1+/- Apc1638N/+ mutant mice; (iii) sulindac increased tumors in the cecum of all mice regardless of genetic background; (iv) sulindac decreased inflammation in the small intestine of Apc1638N/+ mice, but it increased inflammation in the small intestine of Mlh1+/- mice and Mlh1+/- Apc1638N/+ mice and (v) sulindac enhanced inflammation in the cecum of all mutant mice. Findings indicate that the effects of sulindac in the intestine of these mutant mouse models are probably related to genetic background and appear to be associated with its inflammatory-inducing response.",
author = "Osamu Itano and Kan Yang and Kunhua Fan and Naoto Kurihara and Hiroharu Shinozaki and Sadanori Abe and Bo Jin and Claudia Gravaghi and Winfried Edelmann and Augenlicht, {Leonard H.} and Levy Kopelovich and Raju Kucherlapati and Sergio Lamprecht and Martin Lipkin",
year = "2009",
doi = "10.1093/carcin/bgp200",
language = "English (US)",
volume = "30",
pages = "1923--1926",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "11",

}

TY - JOUR

T1 - Sulindac effects on inflammation and tumorigenesis in the intestine of mice with Apc and Mlh1 mutations

AU - Itano, Osamu

AU - Yang, Kan

AU - Fan, Kunhua

AU - Kurihara, Naoto

AU - Shinozaki, Hiroharu

AU - Abe, Sadanori

AU - Jin, Bo

AU - Gravaghi, Claudia

AU - Edelmann, Winfried

AU - Augenlicht, Leonard H.

AU - Kopelovich, Levy

AU - Kucherlapati, Raju

AU - Lamprecht, Sergio

AU - Lipkin, Martin

PY - 2009

Y1 - 2009

N2 - We have previously reported that sulindac, a non-steroidal anti-inflammatory drug, inhibited tumor formation in the small intestine but increased tumors in the colon of ApcMin/+ mice, a model of human familial adenomatous polyposis. To further explore intestinal regional responses, we studied effects of sulindac on additional gene-targeted mouse models of human intestinal tumorigenesis; these were (i) Apc1638N/ mouse (chain termination mutation in exon 15 of the Apc gene); (ii) Mlh1+/- mouse (DNA mismatch repair deficiency, a mouse model of human hereditary non-polyposis colorectal cancer) and (iii) double-heterozygous Mlh1+/- Apc1638N/+ mutant mouse. Mice were fed AIN-76A control diet with or without 0.02% sulindac for 6 months. Intestinal regional tumor incidence, multiplicity, volume and degree of inflammation were used as end points. The results showed the following: (i) sulindac inhibited tumor development in the small intestine of Apc638N/+ mice; (ii) in contrast, sulindac increased tumors in the small intestine of Mlh1 mutant mice, a neoplastic effect which persisted in heterozygous compound Mlh1+/- Apc1638N/+ mutant mice; (iii) sulindac increased tumors in the cecum of all mice regardless of genetic background; (iv) sulindac decreased inflammation in the small intestine of Apc1638N/+ mice, but it increased inflammation in the small intestine of Mlh1+/- mice and Mlh1+/- Apc1638N/+ mice and (v) sulindac enhanced inflammation in the cecum of all mutant mice. Findings indicate that the effects of sulindac in the intestine of these mutant mouse models are probably related to genetic background and appear to be associated with its inflammatory-inducing response.

AB - We have previously reported that sulindac, a non-steroidal anti-inflammatory drug, inhibited tumor formation in the small intestine but increased tumors in the colon of ApcMin/+ mice, a model of human familial adenomatous polyposis. To further explore intestinal regional responses, we studied effects of sulindac on additional gene-targeted mouse models of human intestinal tumorigenesis; these were (i) Apc1638N/ mouse (chain termination mutation in exon 15 of the Apc gene); (ii) Mlh1+/- mouse (DNA mismatch repair deficiency, a mouse model of human hereditary non-polyposis colorectal cancer) and (iii) double-heterozygous Mlh1+/- Apc1638N/+ mutant mouse. Mice were fed AIN-76A control diet with or without 0.02% sulindac for 6 months. Intestinal regional tumor incidence, multiplicity, volume and degree of inflammation were used as end points. The results showed the following: (i) sulindac inhibited tumor development in the small intestine of Apc638N/+ mice; (ii) in contrast, sulindac increased tumors in the small intestine of Mlh1 mutant mice, a neoplastic effect which persisted in heterozygous compound Mlh1+/- Apc1638N/+ mutant mice; (iii) sulindac increased tumors in the cecum of all mice regardless of genetic background; (iv) sulindac decreased inflammation in the small intestine of Apc1638N/+ mice, but it increased inflammation in the small intestine of Mlh1+/- mice and Mlh1+/- Apc1638N/+ mice and (v) sulindac enhanced inflammation in the cecum of all mutant mice. Findings indicate that the effects of sulindac in the intestine of these mutant mouse models are probably related to genetic background and appear to be associated with its inflammatory-inducing response.

UR - http://www.scopus.com/inward/record.url?scp=70849089275&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70849089275&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgp200

DO - 10.1093/carcin/bgp200

M3 - Article

VL - 30

SP - 1923

EP - 1926

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 11

ER -