Effect of zileuton and celecoxib on urinary LTE4 and PGE-M levels in smokers

Arash Mohebati, Ginger L. Milne, Xi Kathy Zhou, Anna J. Duffield-Lillico, Jay O. Boyle, Allison Knutson, Brian P. Bosworth, Philip J. Kingsley, Lawrence J. Marnett, Powel H. Brown, Esther G. Akpa, Eva Szabo, Andrew J. Dannenberg

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

COX-2 and 5-lipoxygenase (5-LO) use arachidonic acid for the synthesis of eicosanoids that have been implicated in carcinogenesis and cardiovascular disease. The ability of celecoxib, a selective COX-2 inhibitor, to redirect arachidonic acid into the 5-LO pathway can potentially reduce its efficacy as a chemopreventive agent and increase the risk of cardiovascular complications. Levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E 4 (LTE4), biomarkers of the COX and 5-LO pathways, are elevated in smokers. Here, we investigated the effects of zileuton, a 5-LO inhibitor, versus zileuton and celecoxib for 6±1 days on urinary PGE-Mand LTE4 levels in smokers. Treatment with zileuton led to an18% decrease in PGE-M levels (P = 0.03); the combination of zileuton and celecoxib led to a 62% reduction in PGE-M levels (P < 0.001). Levels of LTE4 decreased by61%in subjects treated with zileuton alone (P < 0.001) and were unaffected by the addition of celecoxib. Although zileuton use was associated with a small overall decrease in PGE-M levels, increased PGE-M levels were found in a subset (19 of 52) of subjects. Notably, the addition of celecoxib to the 5-LO inhibitor protected against the increase in urinary PGE-M levels (P=0.03). In conclusion, zileuton was an effective inhibitor of 5-LO activity resulting in marked suppression of urinary LTE4 levels and possible redirection of arachidonic acid into the COX-2 pathway in a subset of subjects. Combining celecoxib and zileuton was associated with inhibition of both the COX-2 and 5-LO pathways manifested as reduced levels of urinary PGE-M and LTE4.

Original languageEnglish (US)
Pages (from-to)646-655
Number of pages10
JournalCancer Prevention Research
Volume6
Issue number7
DOIs
StatePublished - Jul 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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