Although
inducible nitric oxide synthase (iNOS) and
nitric oxide (NO) are implicated in
tumor pathology, their role in the early stages of
carcinogenesis is not well defined.
Tumor necrosis factor alpha (
TNFalpha) induces iNOS and NO production in transformation-sensitive JB6 P+, but not in transformation-resistant JB6 P-, mouse epidermal cells. We tested the hypothesis that iNOS, by generating NO and
reactive nitrogen species, mediates
tumor promoter-induced transformation. Specific [N-[3-(aminomethyl)benzyl]
acetamidine (1400W)] and non-specific (N(omega)-methyl-
L-arginine) iNOS inhibitors significantly reduced
TNFalpha-induced NO production in P+ cells but both iNOS inhibitors enhanced
TNFalpha-induced anchorage-independent transformation, thus ruling out a mediator role and suggesting an inhibitor role for NO. Independent support for an inhibitor role came from the observation that the NO donor [(Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (
DETA/NO)] inhibited
TNFalpha- and 12-O-tetradecanoylphorbol-13-acetate-induced transformation.
DETA/NO treatment also suppressed
tumor phenotype in tumorigenic JB6 RT101 (Tx) cells. Higher concentrations of
DETA/NO induced apoptosis. The transformation inhibitory effect of lower
DETA/NO concentrations may be attributable in part to inhibition by NO of
NF-kappaB-dependent but not of AP-1-dependent transcription.
IN CONCLUSION: (a) induction of iNOS and NO production does not mediate but actually prevents
tumor promotion; (b) iNOS inhibitors enhance the transformation response, and therefore appear not to be appropriate as
chemoprevention agents; and (c) NO has both chemopreventive and tumoricidal effects, suggesting promise in
cancer chemoprevention and
therapy.