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

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

Research output: Contribution to journalArticle

24 Scopus citations

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.

Original languageEnglish (US)
Article numbere0121402
JournalPloS one
Volume10
Issue number3
DOIs
StatePublished - Mar 6 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Gounaris, E., Heiferman, M. J., Heiferman, J. R., Shrivastav, M., Vitello, D., Blatner, N. R., Knab, L. M., Phillips, J. D., Cheon, E. C., Grippo, P. J., Khazaie, K., Munshi, H. G., & Bentrem, D. J. (2015). Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation. PloS one, 10(3), [e0121402]. https://doi.org/10.1371/journal.pone.0121402