title: Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: 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.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sood
authors.forename: Su
authors.initials: S
authors.lastname: Wang
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Fang
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Sun
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Chen
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000008:administration & dosage; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000096:biosynthesis*; D016718:Arachidonic Acid / Q000378:metabolism; D002273:Carcinogens / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control*; D000068579:Celecoxib; D002471:Cell Transformation, Neoplastic; D018890:Chemoprevention; D006224:Cricetinae; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D008647:Mesocricetus; D009062:Mouth Neoplasms / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control*; D009374:Neoplasms, Experimental; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis*; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D011720:Pyrazoles; D013449:Sulfonamides; D016718:Arachidonic Acid; D015127:9,10-Dimethyl-1,2-benzanthracene; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; C063449:zileuton; D006918:Hydroxyurea