Suppression of intestinal polyposis in Apcmin/+ mice by targeting the nitric oxide or poly(ADP-ribose) pathways

Jon G. Mabley, Pál Pacher, Peter Bai, Rebecca Wallace, Sunali Goonesekera, Laszlo Virag, Garry J. Southan, Csaba Szabo

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Min mice have a germ-line nonsense mutation at codon 850 of the adenomatous polyposis coli (Apc) gene. These mice spontaneously develop multiple polyps in the small and large intestine at the age of 10-12 weeks. The aim of this study was to assess the role of reactive nitrogen species and poly(ADP-ribose) synthetase in tumorogenesis. Oxidative stress was found to be increased in the mucosa of the small intestine of Apcmin/+ mice with a concomitant increase in intestinal polyposis over control mice. Pharmacological inhibition of inducible nitric oxide synthase (NOS) with guanidinoethyldisulfide (GED) or stimulation of the breakdown of the nitrogen reactive species peroxynitrite using a potent decomposition catalyst, FP 15, reduced both the intestinal tumor load and the oxidative stress associated with intestinal polyposis in Apcmin/+ mice. Surprisingly, pharmacological inhibition of poly(ADP-ribose) synthetase by the phenanthridinone derivative PJ 34 also reduced the intestinal polyposis and oxidative stress in these mice, possibly through the inhibition of induction of nitric oxide synthase. These results suggest that reactive nitrogen species particularly peroxynitrite play a pivotal role in development of intestinal polyposis and that strategies to reduce both the oxidative stress and the formation of these radical species may be potential chemopreventive approaches for colorectal cancers.

Original languageEnglish (US)
Pages (from-to)107-116
Number of pages10
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume548
Issue number1-2
DOIs
StatePublished - Apr 14 2004
Externally publishedYes

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Intestinal Polyposis
Poly Adenosine Diphosphate Ribose
Nitric Oxide
Reactive Nitrogen Species
Oxidative Stress
Peroxynitrous Acid
Ligases
Small Intestine
Pharmacology
APC Genes
Germ-Line Mutation
Nonsense Codon
Large Intestine
Nitric Oxide Synthase Type II
Polyps
Tumor Burden
Codon
Nitric Oxide Synthase
Colorectal Neoplasms
Mucous Membrane

Keywords

  • Apc mice
  • Nitric oxide
  • Oxidative stress
  • Peroxynitrite
  • Poly(ADP-ribose) synthetase

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Molecular Biology

Cite this

Suppression of intestinal polyposis in Apcmin/+ mice by targeting the nitric oxide or poly(ADP-ribose) pathways. / Mabley, Jon G.; Pacher, Pál; Bai, Peter; Wallace, Rebecca; Goonesekera, Sunali; Virag, Laszlo; Southan, Garry J.; Szabo, Csaba.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 548, No. 1-2, 14.04.2004, p. 107-116.

Research output: Contribution to journalArticle

Mabley, Jon G. ; Pacher, Pál ; Bai, Peter ; Wallace, Rebecca ; Goonesekera, Sunali ; Virag, Laszlo ; Southan, Garry J. ; Szabo, Csaba. / Suppression of intestinal polyposis in Apcmin/+ mice by targeting the nitric oxide or poly(ADP-ribose) pathways. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2004 ; Vol. 548, No. 1-2. pp. 107-116.
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