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

Elias Gounaris,Khashayarsha Khazaie,Jeffrey R Heiferman,Manisha Shrivastav,Joseph D Phillips,David J Bentrem,Dominic Vitello,Hidayatullah G Munshi,Eric C Cheon,Paul J Grippo,Nichole R Blatner,Lawrence M Knab,Michael J Heiferman

doi:10.1371/journal.pone.0121402

Elias Gounaris, Khashayarsha Khazaie + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0121402

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Journal: PloS one	Publication Date: Mar 6, 2015
Citations: 77	License type: CC BY 4.0

Affiliation: Northwestern University, Jesse Brown VA Medical Center

Abstract

PurposeLeukotrienes 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 DesignIn 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.ResultsZileuton-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.ConclusionsThis 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.

Highlights

Increased chronic colitis predispose patients to colorectal cancer (CRC) and colitis-associated cancer (CAC) [1,2,3,4,5]
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
We examined the effect of pharmacological inhibition of 5-LO with Zileuton in mice on intestinal polyposis

Summary

Results

A group of 6 APCΔ468/+ mice were fed with chow AIN93G containing Zileuton (Zileuton; 1,200mg/kg). Mice from the Zileuton group developed 2.6 times fewer polyps in the small intestine and half the number of polyps in the colon (Fig. 1A,B). The number of the colon polyps in the Zileuton-treated mice, as calculated with NIRF reflectance fluorescence was at least 2.5 fold less than the polyps in the control group (Fig. 1D). In the polyps of the small intestine, the number of BrdU+ cells was 30% lower in the Zileuton group compared to the mice of the control group, while in the colon polyps the frequency of the dividing cells was over 2-fold lower in the Zileuton group than the control group (Fig. 2A). To evaluate whether monocytes contributed to the reduction in inflammation in the Zileuton-fed mice, we analyzed single cell suspensions of spleens and MLNs with flow cytometry (Fig. 4B). The mean concentration of LTB4 was more than 2-fold higher in the cancerous tissue extracts than the LTB4 concentation in the extracts of normal neighboring tissues (Fig. 5D)

Conclusions

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