This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, X. Articles by Yang, C. S. Search for Related Content PubMed PubMed Citation Articles by Chen, X. Articles by Yang, C. S.

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

¹ 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; ² Section of General Thoracic Surgery, Department of Surgery and ³ Department of Pathology, University of Michigan, Ann Arbor, Michigan; ⁴ Division of Biometrics, University of Medicine and Dentistry of New Jersey School of Public Health, New Brunswick, New Jersey; and ⁵ Chemoprevention Branch, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

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 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.

This article has been cited by other articles:

				F. Cianchi, C. Cortesini, L. Magnelli, E. Fanti, L. Papucci, N. Schiavone, L. Messerini, A. Vannacci, S. Capaccioli, F. Perna, et al. Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells. Mol. Cancer Ther., November 1, 2006; 5(11): 2716 - 2726. [Abstract] [Full Text] [PDF]

				Z. Sun, S. Sood, N. Li, D. Ramji, P. Yang, R. A. Newman, C. S. Yang, and X. Chen Involvement of the 5-lipoxygenase/leukotriene A4 hydrolase pathway in 7,12-dimethylbenz[a]anthracene (DMBA)-induced oral carcinogenesis in hamster cheek pouch, and inhibition of carcinogenesis by its inhibitors Carcinogenesis, September 1, 2006; 27(9): 1902 - 1908. [Abstract] [Full Text] [PDF]

				A. L. Mayburd, A. Martlinez, D. Sackett, H. Liu, J. Shih, J. Tauler, I. Avis, and J. L. Mulshine Ingenuity Network-Assisted Transcription Profiling: Identification of a New Pharmacologic Mechanism for MK886. Clin. Cancer Res., March 15, 2006; 12(6): 1820 - 1827. [Abstract] [Full Text] [PDF]

				A. Hoque, S. M. Lippman, T.-T. Wu, Y. Xu, Z. D. Liang, S. Swisher, H. Zhang, L. Cao, J. A. Ajani, and X.-c. Xu Increased 5-lipoxygenase expression and induction of apoptosis by its inhibitors in esophageal cancer: a potential target for prevention Carcinogenesis, April 1, 2005; 26(4): 785 - 791. [Abstract] [Full Text] [PDF]

				N. Li, S. Sood, S. Wang, M. Fang, P. Wang, Z. Sun, C. S. Yang, and X. Chen Overexpression of 5-Lipoxygenase and Cyclooxygenase 2 in Hamster and Human Oral Cancer and Chemopreventive Effects of Zileuton and Celecoxib Clin. Cancer Res., March 1, 2005; 11(5): 2089 - 2096. [Abstract] [Full Text] [PDF]