Abstract 811: Co-inhibition of cyclooxygenase-2 and inducible nitric oxide synthase prevents N-nitrosomethylbenzylamine-induced esophageal squamous cell carcinoma in rats

Abstract

Abstract Hyperactivation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) has been observed separately in esophageal squamous cell carcinoma (ESCC) in rats that is induced by N-nitrosomethylbenzylamine (NMBA), a powerful carcinogen found in some human diets. In approach to discover new prevention strategies for ESCC, celecoxib and S,S′-1,4-phenylene-bis(1,2-ethanediyl)bis-isothiourea (PBIT), selective inhibitors respectively to COX-2 and iNOS, were evaluated in the NMBA-rat preclinical esophageal cancer model. F344 rats were treated with NMBA (0.30mg/kg b.w.) three times per week for five weeks. Seventy-two hours after the last NMBA treatment, rats were fed with control diet with or without different doses of celecoxib and PBIT. At week 35, rats were sacrificed and esophageal tumors were counted. Celecoxib (1000 ppm) or PBIT (100 ppm) alone, and a combination treatment with celecoxib (500 ppm) and PBIT (50 ppm), significantly decreased the NMBA-induced tumor multiplicity (from 4.73 ± 0.45 to 2.00 ± 0.25, 1.89 ± 0.23, and 1.61 ± 0.27, respectively), which were accompanied by the inhibition of transcription, translation and kinase activity of both COX-2 and iNOS in all these treatments. By using this COX-2/iNOS co-inhibition strategy, celecoxib/PBIT combination inhibited cancerous esophagus cell proliferation by immunohistochemistry staining of PCNA, and decreased c-Myc expression in NMBA-induced papillomas by Western blot analysis. In addition, the histopathological examination of rat esophagus showed that celecoxib/PBIT combination significantly prevented NMBA-induced tumor transformation (from 8.373% to 1.765%). In conclusion, our results indicated that co-inhibition of COX-2 and iNOS by Celecoxib/PBIT combination prevented NMBA-induced ESCC in rats, which represents a new means of esophageal cancer prevention. (Supported by NIH/NCI RO1 CA131073-01A1). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 811. doi:10.1158/1538-7445.AM2011-811