Results from epidemiological studies indicate that long-term intake of non-steroidal anti-inflammatory drugs, which inhibit cyclooxygenase (COX) enzymes involved in prostaglandin biosynthesis, reduces the risk of several forms of human malignancies. Expression of COX-2 in tumors is known to be associated with enhanced angiogenesis, suppression of host immunity, and tumor invasion. Genetic or pharmacological inhibition of COX-2 has been shown to protect against experimentally-induced carcinogenesis and to reduce the growth of xenografted tumors in animal models. A number of studies also revealed that COX-2 inhibition suppresses proliferation, metastatic potential, and other functions of cancer cell lines. Thus, it is conceivable that targeted inhibition of abnormally or improperly elevated COX-2 provides one of the most effective and promising strategies for cancer therapy. In this review, the involvement of COX-2 in the tumorigenesis of oral cancers and the potential mechanisms of tumor suppressive effects of COX-2 inhibition are discussed.

Results from epidemiological studies indicate that long-term intake of non-steroidal anti-inflammatory drugs, which inhibit cyclooxygenase (COX) enzymes involved in prostaglandin biosynthesis, reduces the risk of several forms of human malignancies. Expression of COX-2 in tumors is known to be associated with enhanced angiogenesis, suppression of host immunity, and tumor invasion. Genetic or pharmacological inhibition of COX-2 has been shown to protect against experimentally-induced carcinogenesis and to reduce the growth of xenografted tumors in animal models. A number of studies also revealed that COX-2 inhibition suppresses proliferation, metastatic potential, and other functions of cancer cell lines. Thus, it is conceivable that targeted inhibition of abnormally or improperly elevated COX-2 provides one of the most effective and promising strategies for cancer therapy. In this review, the involvement of COX-2 in the tumorigenesis of oral cancers and the potential mechanisms of tumor suppressive effects of COX-2 inhibition are discussed.

The environmental contaminant benzo[a]pyrene (B[a]P) has been regarded as one of the pathogens of oral premalignant and malignant lesions. To elucidate the pathogenesis of oral premalignancies, B[a]P-induced dysplasia of the murine tongue was investigated for G1-associated cell cycle regulation. B[a]P solution was applied orally up to six weeks to induce epithelial dysplasia of the tongue. BrdU incorporation and the expression of p21, cyclin D1, and CDK4 were examined by immunohistochemistry and Western blotting. Rb phosphorylation and E2F-Rb binding were examined by immunoprecipitation and Western blotting. B[a]P treatment resulted in dysplastic changes and active DNA synthesis in the tongue epithelia. Immunohistochemical analyses showed p21 up-regulation and cyclin D1/CDK4 overexpression in B[a]P-induced dysplasia. Rb hyperphosphorylation and E2F release were caused by B[a]P treatment. Thus, dysregulation of G1-phase regulation is likely to be an important event in the development of oral epithelial dysplasia in mice.