Abstract
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. 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. 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. 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.
Highlights
Oral cancer is a common neoplasm worldwide, in developing countries
The results clearly showed that both 5-Lox and Cyclooxygenase 2 (Cox2) played important roles in oral carcinogenesis
This expression pattern indicated that 5-Lox overexpression was an early event in DMBA-induced oral carcinogenesis
Summary
Oral cancer is a common neoplasm worldwide, in developing countries. In the United States, oral cancer incidence and mortality rates have been increasing in recent years, especially among young males [1]. Previous studies on a ‘‘complete’’ 7,12-dimethylbenz[a]anthracene (DMBA) – induced hamster cheek pouch model suggested chemopreventive effects of nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, indomethacin, and aspirin) on oral cancer. Chemopreventive effects of 5-Lox pathway inhibitors have been shown in animal models of lung [27], skin [28], pancreatic [29, 30], and esophageal cancers [25]. It is unknown whether the 5-Lox pathway plays an important role in oral carcinogenesis. We showed overexpression of 5-Lox and Cox in cancers of DMBA-treated hamster cheek pouch and human oral cavity. Zileuton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox inhibitor), either alone or in combination, were topically applied on the DMBA-treated hamster oral mucosa, to test their chemopreventive effects on oral carcinogenesis at the post-initiation stage
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