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

E Gounaris, MJ Heiferman, JR Heiferman… - PloS one, 2015 - journals.plos.org
E Gounaris, MJ Heiferman, JR Heiferman, M Shrivastav, D Vitello, NR Blatner, LM Knab…
PloS one, 2015journals.plos.org
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 …
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.
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