Prevention of upper aerodigestive tract cancer in zinc‐deficient rodents: Inefficacy of genetic or pharmacological disruption of COX‐2

Abstract

Zinc deficiency in humans is associated with an increased risk of upper aerodigestive tract (UADT) cancer. In rodents, zinc deficiency predisposes to carcinogenesis by causing proliferation and alterations in gene expression. We examined whether in zinc-deficient rodents, targeted disruption of the cyclooxygenase (COX)-2 pathway by the COX-2 selective inhibitor celecoxib or by genetic deletion prevent UADT carcinogenesis. Tongue cancer prevention studies were conducted in zinc-deficient rats previously exposed to a tongue carcinogen by celecoxib treatment with or without zinc replenishment, or by zinc replenishment alone. The ability of genetic COX-2 deletion to protect against chemically-induced forestomach tumorigenesis was examined in mice on zinc-deficient versus zinc-sufficient diet. The expression of 3 predictive biomarkers COX-2, nuclear factor (NF)-j B p65 and leukotriene A 4 hydrolase (LTA 4 H) was examined by immunohistochemistry. In zinc-deficient rats, celecoxib without zinc replenishment reduced lingual tumor multiplicity but not progression to malignancy. Celecoxib with zinc replenishment or zinc replenishment alone significantly lowered lingual squamous cell carcinoma incidence, as well as tumor multiplicity. Celecoxib alone reduced overexpression of the 3 biomarkers in tumors slightly, compared with intervention with zinc replenishment. Instead of being protected, zinc-deficient COX-2 null mice developed significantly greater tumor multiplicity and forestomach carcinoma incidence than wild-type controls. Additionally, zinc-deficient COX-22/2 forestomachs displayed strong LTA 4 H immunostaining, indicating activation of an alternative pathway under zinc deficiency when the COX-2 pathway is blocked. Thus, targeting only the COX-2 pathway in zinc-deficient animals did not prevent UADT carcinogenesis. Our data suggest zinc supplementation should be more thoroughly explored in human prevention clinical trials for UADT cancer. ' 2007 Wiley-Liss, Inc.Key words: zinc deficiency; upper aerodigestive tract cancer; chemoprevention; COX-2; COX-2 null mice Upper aerodigestive tract (UADT) cancer, including esophageal and oral cancer, is an important cause of morbidity and mortality worldwide. 1 With a 5-year survival of 10%, esophageal cancers are deadly. The prognosis of oral cancer, the major site being the tongue, is equally dismal, with an increasing incidence worldwide, particularly in young adults. 2 Patients with oral cancer have a high mortality rate, because of field cancerization effects that result in second primary tumors, particularly in the esophagus. 3,4 Thus, new chemopreventive and therapeutic approaches are much needed to prevent and treat these deadly cancers.While chronic alcohol consumption and tobacco use are the major risk factors for UADT cancer, epidemiologic and clinical studies have implicated dietary zinc deficiency (ZD) in the etiology of esophageal squamous cell carcinoma (SCC) and head and neck SCC. [5][6][7][8][9] In 2005, Abnet et al. 10 provided the strongest evidence of an a...

Ethanol Promotes Chemically Induced Oral Cancer in Mice through Activation of the 5-Lipoxygenase Pathway of Arachidonic Acid Metabolism

“…This is consistent with previous studies showing that genetic or pharmacological disruption of Cox-2 activated the 5-Lox pathway (41, 42), and knockout of 5-Lox or 5-Lox activating protein increased the Cox metabolites produced by inflammatory cells (43, 44). Our data support the idea of combination therapy or chemoprevention.…”

“…Populations of infiltrating inflammatory cells in the oral epithelium are also different in these two models (35). The 4NQO model has been more and more widely used for studying the roles of genes/pathways in, and preventive/therapeutic effects on, oral carcinogenesis because of its convenience of use and potential use of genetically modified mice (36–41). Parallel studies with both the 4NQO model and the DMBA model may generate novel findings, which may provide insights on different pathologies of human oral cancer.…”

Zinc deficiency activates S100A8 inflammation in the absence of COX‐2 and promotes murine oral‐esophageal tumor progression

“…After a week, all mice were sacrificed. This experimental regimen produced unbridled cell proliferation in ZD: Cox-2 −/− forestomach 16. Tongue and forestomach were isolated and cut into two portions.…”

“…Thirtynine 4-week old Cox-2 −/− mice were fed a ZD diet to form the ZD: Cox-2 −/− group. After 4 weeks, the mice received 3 intragastric doses of NMBA (2 mg/kg body weight, twice weekly), a regimen that produced a high tumor outcome in ZD: Cox-2 −/− mice 16. A day after the 3 rd dose, 18 mice were switched to a ZS diet to form the ZR: Cox-2 −/− group, which were given an intragastric dose of Zn gluconate weekly for 14 weeks (0.04 mg Zn).…”

“…ZD rats rapidly develop esophageal tumors after a single exposure to the environmental carcinogen N -nitrosomethylbenzylamine (NMBA)15 and concurrent tongue, esophageal, and forestomach tumors with exposure to the tongue carcinogen 4-nitroquinoline 1-oxide (NQO) 13. Zn-replenishment (ZR) reverses cell proliferation, corrects gene expression, and inhibits carcinogenesis 14-16…”