Nitric oxide synthase and skin tumor promotion

Up-regulation of inducible form of nitric oxide (NO)-synthase and increased production of NO has been shown to occur in many pathological conditions associated with inflammatory responses. In this study we show that topical application of skin tumor promoters, which are known to produce inflammatory response, down-regulate the constitutive form of NO-synthase in SENCAR mouse epidermis. The phorbol type of tumor promoters viz 12-0-tetradecanoylphorbol-13-acetate (TPA) and mezerein produced greater inhibitory effects than the non phorbol tumor promoters viz anthralin, n-dodecane, benzoyl peroxide and okadaic acid. Pretreatment of the skin with a polyphenolic fraction isolated from green tea, which possesses strong antioxidant activity, almost completely restored the inhibitory response. We suggest that the constitutive NO-synthase activity may play an important role in tumor promoter-caused oxidative burst during the promotion stage of multistage skin carcinogenesis, and that antioxidants may also target their anti-tumor promoting effect via attenuating the NO-synthase pathway.