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Suppression of intestinal polyposis in Apc(Min/+) mice by inhibiting nitric oxide production
1Department of Pathology, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul, 122-704, Korea.
Abstract:
Inducible nitric oxide synthase (iNOS) was shown to be expressed in normal mucosa and adenoma of small and large intestines of Apc(Min/+) mice by reverse transcription-PCR and immunohistochemistry. Administration of the iNOS inhibitor aminoguanidine (1.5 g/liter) in drinking water or an L-arginine-deficient diet to Apc(Min/+) mice resulted in a significant decrease in adenoma development in the small but not the large intestine. Similarly, iNOS-gene knockout Apc(Min/+) mice (Apc(Min/+) iNOS(-/-) or Apc(Min/+) iNOS(-/+)) developed significantly fewer adenomas in both small and large intestines than Apc(Min/+) iNOS(+/+) mice. These results suggest that iNOS-selective inhibitors could be used as a potential chemopreventive agent for colorectal cancers.
Insights
Inducible nitric oxide synthase (iNOS) is present in intestinal adenomas. Inhibiting iNOS or its gene significantly reduced tumor development in mice, suggesting iNOS inhibitors as potential colorectal cancer chemopreventive agents.
Area of Science:
- Gastroenterology
- Oncology
- Molecular Biology
Background:
- Inducible nitric oxide synthase (iNOS) expression is observed in normal and adenomatous tissues of the small and large intestines.
- Apc(Min/+) mice serve as a model for intestinal adenoma development, mimicking human colorectal cancer.
- Nitric oxide plays a complex role in tumorigenesis, necessitating investigation into iNOS's specific contribution.
Purpose of the Study:
- To investigate the role of inducible nitric oxide synthase (iNOS) in the development of intestinal adenomas in Apc(Min/+) mice.
- To evaluate the efficacy of iNOS inhibition as a chemopreventive strategy against colorectal cancer.
Main Methods:
- Reverse transcription-PCR and immunohistochemistry were used to detect iNOS expression in intestinal tissues.
- Apc(Min/+) mice were treated with an iNOS inhibitor (aminoguanidine) or an L-arginine-deficient diet.
- Apc(Min/+) mice with iNOS gene knockout were analyzed for adenoma development.
Main Results:
- iNOS expression was confirmed in normal mucosa and adenomas of the small and large intestines in Apc(Min/+) mice.
- Inhibition of iNOS via aminoguanidine or L-arginine deficiency significantly reduced adenoma formation in the small intestine, but not the large intestine.
- Apc(Min/+) mice lacking iNOS (knockout) exhibited significantly fewer adenomas in both the small and large intestines compared to controls.
Conclusions:
- iNOS plays a significant role in the development of intestinal adenomas in Apc(Min/+) mice.
- Targeting iNOS may represent a viable chemopreventive approach for colorectal cancers.
- Further research into iNOS-selective inhibitors is warranted for colorectal cancer prevention.