Abstract 819: Black raspberries inhibit N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis through down-regulation of MAPK and NFκB pathways

Abstract

Abstract Esophageal cancer is the 6th most common cancer worldwide. Our laboratory has used a rodent preclinical model of esophageal squamous cell carcinoma to identify putative chemopreventive agents for this disease and to determine their mechanisms of action. In our previous studies, we found that freeze-dried black raspberry (BRB) significantly suppressed N-nitrosomethylbenzylamine (NMBA)-induced tumor development in rat esophagus, at least in part by inhibition of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), c-Jun and vascular endothelial growth factor (VEGF). The mitogen-activated protein kinase (MAPK) and nuclear factor κB (NFκB) pathways play important roles in certain aspects of carcinogenesis. However, their roles and effects of BRB on these two pathways in the NMBA model of rat esophageal tumorigenesis have not been investigated yet. In the present study, F344 rats were treated with NMBA (0.30 mg/kg b.w.) three times per week for 5 weeks. After 72 hours, animals were fed AIN-76A diet or AIN-76A diet containing 5% BRB. At week 35, rats were sacrificed and esophageal tumors were counted. The incidence of esophageal tumors was decreased from 100% in NMBA-treated rats to 81.48% (P < 0.05) in rats treated with NMBA+5% BRB. The tumor multiplicity was reduced in rats fed 5% BRB to an average of 1.44 ± 0.25 (P < 0.001) tumors per rat compared with 4.73 ± 2.70 in rats fed the control diet. In preneoplastic lesions, BRB decreased protein expression of phospho-NFκB-p65, phospho-IkBα, phospho-MAPK-p38, phospho-MAPK-p44/42 and phosphor-SAPK/JNK from 4.2-fold, 3.9-fold, 3.1-fold, 4.7-fold and 5.5-fold in rats fed the control diet to 1.2-fold (P < 0.005), 1.3-fold (P < 0.005), 1.3-fold (P < 0.005), 1.4-fold (P < 0.005) and 1.4-fold (P < 0.005), respectively, in rats fed 5% BRB. In papillomatous lesions, BRB reduced protein expression of phospho-NFκB-p65, phospho-IkBα, phospho-MAPK-p38, phospho-MAPK-p44/42 and phosphor-SAPK/JNK from 5.9-fold, 4.7-fold, 5.7-fold, 5.9-fold and 6.1-fold in rats fed the control diet to 1.3-fold (P < 0.005), 1.5-fold (P < 0.005), 1.6-fold (P < 0.005), 1.5-fold (P < 0.005) and 1.6-fold (P < 0.005), respectively, in rats fed 5% BRB. Our results indicated that both MAPK and NFκB pathways were activated in NMBA-induced tumor development in rats and these activations were significantly inhibited by BRB. Collectively, our data suggest that BRB may offer a relatively nontoxic alternative to the prevention of esophageal cancer in humans. (Supported by 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 819. doi:10.1158/1538-7445.AM2011-819