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 Li, N. Articles by Chen, X. Search for Related Content PubMed PubMed Citation Articles by Li, N. Articles by Chen, X.

Overexpression of 5-Lipoxygenase and Cyclooxygenase 2 in Hamster and Human Oral Cancer and Chemopreventive Effects of Zileuton and Celecoxib

¹ Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, New Jersey; ² Division of Food Toxicology, Institute of Nutrition and Food Hygiene, Chinese Center for Disease Control; and ³ Department of Oral Medicine, Beijing Hospital for Stomatology, Beijing, P.R. China

Requests for reprints: Xiaoxin Chen, Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854. Phone: 732-445-3400, ext. 259; Fax: 732-445-0687; E-mail: xiaochen{at}rci.rutgers.edu.

Purpose: Previous studies have suggested an important role of aberrant arachidonic acid metabolism, especially the cyclooxygenase (Cox) pathway, in oral carcinogenesis. However, it is unknown whether the 5-lipoxygenase (5-Lox) pathway contributes to oral carcinogenesis, and whether combination of inhibitors of both pathways may have synergistic or additive effects of chemoprevention.

Experimental Design: 5-Lox expression was examined in 7,12-dimethylbenz[a]anthracene (DMBA)–induced hamster and human oral cancer tissues by immunohistochemistry, and Cox2 expression was investigated in hamster oral tissues using in situ hybridization. Zileuton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor), either alone or in combination, were investigated for their chemopreventive effects on the DMBA-induced hamster model at the post-initiation stage through topical application.

Results: 5-Lox was overexpressed during oral carcinogenesis in hamsters and humans, as well as Cox2 in the hamster tissues. In a chemoprevention study using the post-initiation DMBA model, incidence of hamster oral squamous cell carcinoma was reduced from 76.9% (20 of 26) to 45.8% (11 of 24, P < 0.05) and 32.1% (9 of 28, P < 0.01) by 3% and 6% topical zileuton, respectively; and to 57.6% (15 of 26, P > 0.05) and 50% (12 of 24, P < 0.05) by 3% and 6% topical celecoxib, respectively. When used in combination, celecoxib and zileuton (3% of each) had an additive inhibitory effect on the incidence of squamous cell carcinoma (36%, 9 of 25, P < 0.01). Other pathologic variables and the levels of leukotriene B4 and prostaglandin E2 of the hamster tissues were reduced as well.

Conclusions: The results clearly showed that both 5-Lox and Cox2 played important roles in oral carcinogenesis. Zileuton and celecoxib prevented oral carcinogenesis at the post-initiation stage through their inhibitory effects on arachidonic acid metabolism.

Key Words: oral cancer • 5-lipoxygenase • cyclooxygenase 2 • hamster • 7,12-dimethylbenz[a]anthracene

This article has been cited by other articles:

				W. Jian, S. H. Lee, M. V. Williams, and I. A. Blair 5-Lipoxygenase-mediated Endogenous DNA Damage J. Biol. Chem., June 19, 2009; 284(25): 16799 - 16807. [Abstract] [Full Text] [PDF]

				P. Yang, Z. Sun, D. Chan, C. A. Cartwright, M. Vijjeswarapu, J. Ding, X. Chen, and R. A. Newman Zyflamend(R) reduces LTB4 formation and prevents oral carcinogenesis in a 7,12-dimethylbenz[{alpha}]anthracene (DMBA)-induced hamster cheek pouch model Carcinogenesis, November 1, 2008; 29(11): 2182 - 2189. [Abstract] [Full Text] [PDF]

				L. G. Melstrom, D. J. Bentrem, M. R. Salabat, T. J. Kennedy, X.-Z. Ding, M. Strouch, S. M. Rao, R. C. Witt, C. A. Ternent, M. S. Talamonti, et al. Overexpression of 5-Lipoxygenase in Colon Polyps and Cancer and the Effect of 5-LOX Inhibitors In vitro and in a Murine Model Clin. Cancer Res., October 15, 2008; 14(20): 6525 - 6530. [Abstract] [Full Text] [PDF]

				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]

				C. P. Schroeder, H. Kadara, D. Lotan, J. K. Woo, H.-Y. Lee, W. K. Hong, and R. Lotan Involvement of Mitochondrial and Akt Signaling Pathways in Augmented Apoptosis Induced by a Combination of Low Doses of Celecoxib and N-(4-Hydroxyphenyl) Retinamide in Premalignant Human Bronchial Epithelial Cells Cancer Res., October 1, 2006; 66(19): 9762 - 9770. [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]