Overexpression of 5-lipoxygenase in rat and human esophageal adenocarcinoma and inhibitory effects of zileuton and celecoxib on carcinogenesis.
OBJECTIVE
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.


METHODS
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 B4 and prostaglandin E2 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.
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, USA. xiaochen@rci.rutgers.edu
Xiaoxin
X
Chen
Su
S
Wang
Nan
N
Wu
Sandeep
S
Sood
Peng
P
Wang
Zhe
Z
Jin
David G
DG
Beer
Thomas J
TJ
Giordano
Yong
Y
Lin
Wei-Chung J
WC
Shih
Ronald A
RA
Lubet
Chung S
CS
Yang
D000230:Adenocarcinoma / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000714:Anastomosis, Surgical / Q000009:adverse effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis*; D001835:Body Weight / Q000187:drug effects; D000068579:Celecoxib; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004938:Esophageal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D000068579:Celecoxib; D015232:Dinoprostone; C063449:zileuton; D006918:Hydroxyurea