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Carcinogenesis Advance Access originally published online on April 21, 2006
Carcinogenesis 2006 27(9):1902-1908; doi:10.1093/carcin/bgl039
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Zheng Sun1,2,{dagger}, Sandeep Sood3,{dagger}, Ning Li4, Divya Ramji3, Peiying Yang5, Robert A. Newman5, Chung S. Yang3 and Xiaoxin Chen1,2,3,*

1 Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University NC 27707, USA
2 Faculty of Stomatology, Capital University of Medical Sciences Beijing 100050, China
3 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, USA
4 Division of Food Toxicology, Institute of Nutrition and Food Hygiene, Chinese Center for Disease Control Beijing 100050, China
5 Pharmaceutical Development Center, UT M.D. Anderson Cancer Center 8000 El Rio, Houston, TX 77054, USA

*To whom correspondence and requests for reprints should be addressed at: Cancer Research Program, Julius L. Chambers Biomedical/Biotechnology Research Institute, North Carolina Central University, 700 George Street, Durham, NC 27707, USA. Tel: +1 919 530 6425; Fax: +1 919 530 7998; Email: lchen{at}nccu.edu.

Previous studies have shown that aberrant arachidonic acid (AA) metabolism, especially cyclooxygenase-2 (Cox-2) and 5-lipoxygenase (5-Lox) pathways, are activated during oral carcinogenesis, and can be targeted for cancer prevention. This study was designed to investigate the importance of 5-Lox/leukotriene A4 hydrolase (LTA4H) pathway of AA metabolism in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis. In a short-term study, topical application of DMBA for 3 weeks induced severe inflammation and aberrant AA metabolism. Subsequent topical treatment with zileuton, celecoxib, or their combination for 1 week significantly suppressed aberrant AA metabolism and cell proliferation in the oral epithelium. Interestingly, zileuton was effective in inhibiting biosynthesis of multiple AA metabolites, including leukotriene B4 (LTB4), 5-, 12-, 15-hydroxyeicosatetraenoic acid and prostaglandin E2 (PGE2), while celecoxib only suppressed PGE2 biosynthesis significantly at a high dose. In a long-term carcinogenesis study topical application of LTB4 or PGE2 enhanced oral carcinogenesis by increasing the incidence and volume of visible tumors, and the incidence of squamous cell carcinoma (SCC). To further examine the role of LTB4 in oral carcinogenesis, two LTA4H inhibitors, bestatin and SA6541, were evaluated in a long-term chemoprevention experiment. Both agents significantly inhibited SCC, and such an inhibition correlated with reduced levels of LTB4 in hamster cheek pouch. In summary, our studies have demonstrated that 5-Lox/LTA4H pathway is one of the major AA-metabolizing pathways involved in DMBA-induced oral carcinogenesis in hamsters, and may be targeted for chemoprevention.


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