Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib.

Abstract

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.

• Authors: Ning Li, Sandeep Sood, Su Wang, Mingzhu Fang, Peng Wang, Zheng Sun, Chung S Yang, Xiaoxin Chen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 5 Pg. 2089-96 (Mar 01 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15756036 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carcinogens
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Lipoxygenase Inhibitors
• Membrane Proteins
• Pyrazoles
• Sulfonamides
• Arachidonic Acid
• 9,10-Dimethyl-1,2-benzanthracene
• Arachidonate 5-Lipoxygenase
• Cyclooxygenase 2
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Celecoxib
• zileuton
• Hydroxyurea

Topics

• 9,10-Dimethyl-1,2-benzanthracene (administration & dosage)
• Animals
• Arachidonate 5-Lipoxygenase (biosynthesis)
• Arachidonic Acid (metabolism)
• Carcinogens (administration & dosage)
• Carcinoma, Squamous Cell (genetics, physiopathology, prevention & control)
• Celecoxib
• Cell Transformation, Neoplastic
• Chemoprevention
• Cricetinae
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (pharmacology)
• Disease Models, Animal
• Humans
• Hydroxyurea (analogs & derivatives, pharmacology)
• Immunohistochemistry
• In Situ Hybridization
• Lipoxygenase Inhibitors (pharmacology)
• Male
• Membrane Proteins
• Mesocricetus
• Mouth Neoplasms (genetics, physiopathology, prevention & control)
• Neoplasms, Experimental
• Prostaglandin-Endoperoxide Synthases (biosynthesis)
• Pyrazoles (pharmacology)
• Sulfonamides (pharmacology)
• Up-Regulation