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


METHODS
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.
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Elias
E
Gounaris
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Michael J
MJ
Heiferman
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Jeffrey R
JR
Heiferman
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Manisha
M
Shrivastav
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Dominic
D
Vitello
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Nichole R
NR
Blatner
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Lawrence M
LM
Knab
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Joseph D
JD
Phillips
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Eric C
EC
Cheon
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Paul J
PJ
Grippo
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Khashayarsha
K
Khazaie
Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Hidayatullah G
HG
Munshi
Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, United States of America.
David J
DJ
Bentrem
D000818:Animals; D003110:Colonic Neoplasms / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology; D015212:Inflammatory Bowel Diseases / Q000473:pathology / Q000517:prevention & control*; D044483:Intestinal Polyposis / Q000473:pathology / Q000517:prevention & control*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains
D016859:Lipoxygenase Inhibitors; C063449:zileuton; D006918:Hydroxyurea