Suppression of intestinal polyposis in Apcmin/+ mice by targeting the nitric oxide or poly(ADP-ribose) pathways.
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 Apc(min/+) 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 Apc(min/+) 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.
Mabley
Jon G
JG
Inotek Pharmaceuticals Corporation, 100 Cummings Center, Suite 419E, Beverly, MA 01915, USA. jmabley@inotekcorp.com
Pacher
Pál
P
Bai
Peter
P
Wallace
Rebecca
R
Goonesekera
Sunali
S
Virag
Laszlo
L
Southan
Garry J
GJ
Szabó
Csaba
C
D000818:Animals; D003106:Colon / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017491:Genes, APC / Q000502:physiology*; D006146:Guanidines / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000201:enzymology; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D030421:Peroxynitrous Acid / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D006146:Guanidines; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C014363:bis(2-guanidinoethyl)disulfide; D030421:Peroxynitrous Acid; D011064:Poly Adenosine Diphosphate Ribose; D009569:Nitric Oxide; D008315:Malondialdehyde; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011065:Poly(ADP-ribose) Polymerases; D045726:Metalloproteases