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¹ Gene Regulation Section, Basic Research Laboratory; ² Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD; and ³ Basic Research Program, SAIC-Frederick, Frederick, MD

Requests for Reprints: Arindam Dhar, Building 567, Room 180, National Cancer Institute at Frederick, Frederick, MD 21702. Phone: (301) 846-6756; Fax: (301) 846-6907. E-mail: adhar{at}ncifcrf.gov

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 (TNF) 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-methyl-L-arginine) iNOS inhibitors significantly reduced TNF-induced NO production in P+ cells but both iNOS inhibitors enhanced TNF-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 TNF- 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-B-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.

Key Words: iNOS • nitric oxide • NF-B • AP-1 • tumor promoter

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Note: Present address of Cristi Stark: FDA/CBER, Mail Stop HFM-99, Suite 200N, 1401 Rockville Pike, Rockville, MD 20852-1448.

Received 6/ 6/03; revised 8/27/03; accepted 9/ 8/03.

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