Overexpression of 5-Lipoxygenase in Rat and Human Esophageal Adenocarcinoma and Inhibitory Effects of Zileuton and Celecoxib on Carcinogenesis

Abstract

Purpose: Aberrant arachidonic acid (AA) metabolism, especially through the cyclooxygenase (Cox) and 5-lipoxygenase (5-Lox) pathways, has been suggested to play an important role in the development of esophageal adenocarcinoma (EAC). The purpose of this study was to investigate the expression of 5-Lox in EAC of a rat model and in human samples as well as the chemopreventive effects of zileuton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor) in the rat EAC model.Experimental Design: 5-Lox expression in EAC of a rat esophagogastroduodenal anastomosis model and of humans was examined with immunohistochemistry. A chemoprevention study was designed to test whether zileuton and celecoxib could suppress aberrant AA metabolism and esophageal adenocarcinogenesis.Results: With immunohistochemistry, we found that 5-Lox was overexpressed during esophageal adenocarcinogenesis in our rat model and in humans. In the chemoprevention study, EAC incidence was reduced in a dose-dependent manner from 68.8% (11 of 16) to 44.4% (8 of 18; P > 0.05) and 31.3% (5 of 16; P < 0.05) by 500 and 1,000 ppm zileuton, respectively, and to 33.3% (7 of 21; P < 0.05) and 20% (3 of 15; P < 0.05) by 500 and 1,000 ppm celecoxib, respectively. With isobolographic analysis, zileuton and celecoxib, both at a dose of 500 ppm, had an additive effect by reducing the tumor incidence to 16.7% (3 of 18, P < 0.01). Leukotriene B 4 and prostaglandin E 2 levels in the esophageal tissues were also significantly reduced by zileuton and celecoxib.Conclusions: This study clearly demonstrated that 5-Lox and Cox2 play important roles in the development of EAC. Both zileuton and celecoxib had inhibitory effects on esophageal adenocarcinogenesis through inhibition on their respective enzymes of AA metabolism.

Prevention of upper aerodigestive tract cancer in zinc‐deficient rodents: Inefficacy of genetic or pharmacological disruption of COX‐2

“…About 2 decades ago, LTB 4 levels were shown to be >10-fold higher in human and hamster oral SCC than in control tissues, an observation that suggests a possible role for LTB 4 in the pathogenesis of head and neck cancer. 41 More recently, overexpression of LTA 4 H and 5-LOX protein was demonstrated in rat and human esophageal adenocarcinoma 42,43 and hamster and human oral cancer. 44,45 Our data showing overexpression of LTA 4 H protein in lingual lesions/ SCC from ZD rats, as well as in forestomach lesions/SCC from ZD:COX2/2 mice, are consistent with the idea that 5-LOX/ LTA 4 H pathway is of importance in oral carcinogenesis.…”

Inhibition of arachidonic acid metabolism and its implication on cell proliferation and tumour-angiogenesis

“…However, a growing body of investigations support its chemopreventive effects in cancer [130]. A drug with proven selectivity for 12-LOX, Baicalein, has its origin in Chinese herbal medicine and has been found to directly inhibit proliferation and induce apoptosis in human myeloma cells [131].…”

Platelet 12-lipoxygenase and stem cells in Barrett’s esophagus

“…Limited information related to the role and expression of LOX in BE is currently available. 5-LOX showed immunohistochemical overexpression during esophageal adenocarcinogenesis (12). 5-and 12-LOX are regarded as pro-tumorigenic enzymes in colonic carcinogenesis and their overexpression was also described in various types of cancer [(13-16) and references therein].…”