Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation.

Abstract

PURPOSE:

Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice.

EXPERIMENTAL DESIGN:

In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation.

RESULTS:

Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice.

CONCLUSIONS:

This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.

• Authors: Elias Gounaris, Michael J Heiferman, Jeffrey R Heiferman, Manisha Shrivastav, Dominic Vitello, Nichole R Blatner, Lawrence M Knab, Joseph D Phillips, Eric C Cheon, Paul J Grippo, Khashayarsha Khazaie, Hidayatullah G Munshi, David J Bentrem
• Journal: PloS one (PLoS One) Vol. 10 Issue 3 Pg. e0121402 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 25747113 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lipoxygenase Inhibitors
• zileuton
• Hydroxyurea

Topics

• Animals
• Colonic Neoplasms (pathology, prevention & control)
• Disease Models, Animal
• Female
• Humans
• Hydroxyurea (analogs & derivatives, pharmacology)
• Inflammatory Bowel Diseases (pathology, prevention & control)
• Intestinal Polyposis (pathology, prevention & control)
• Lipoxygenase Inhibitors (pharmacology)
• Male
• Mice
• Mice, Mutant Strains