Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol

Abstract

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural product occurring in grapes and various other plants with medicinal properties associated with reduced cardiovascular disease and reduced cancer risk. To evaluate the possibility and potential mechanism(s) of which resveratrol inhibits N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis, 96 F344 male rats were divided into 10 groups and resveratrol (1 and 2 mg/kg) was administered orally or intraperitoneally (i.p.). In the groups in which resveratrol was administered at 2 mg/kg (orally, for 16 weeks), 1 and 2 mg/kg (i.p., for 16 weeks) and 1 mg/kg (i.p., for 20 weeks), the number of NMBA-induced esophageal tumors per rat was significantly reduced to 78, 62, 54 and 48, respectively (P < 0.05), and the size of maximum tumors in each group with resveratrol treatment was also significantly smaller than that in NMBA alone group (P < 0.05). Although the pathological examination did not indicate significantly decreased incidence of carcinomas by administering resveratrol, the tendency of carcinogensis suppression was observed (P = 0.177). Semi-quantitative RT-PCR and ELISA analysis demonstrated that following NMBA treatment, the expression of COX-1 mRNA was strongly present in tumor tissues, while weakly present in non-tissues; the expression of COX-2 mRNA was induced in both tumor and non-tumor tissues. The production of prostaglandin E(2) (PGE(2)) increased approximately 6-fold, compared with the normal esophageal mucosa. The higher expression of COX-1, the up-regulated COX-2 expression and the increased levels of PGE(2) synthesis were all significantly decreased by administering resveratrol. Our study suggests that resveratrol suppressed NMBA-induced rat esophageal tumorigenesis by targeting COXs and PGE(2), and therefore may be a promising natural anti-carcinogenesis agent for the prevention and treatment of human esophageal cancer.

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

“…Several studies demonstrated that resveratrol exhibits strong chemopreventive effects in various experimentally induced tumor models as well as inhibits proliferation and induces apoptosis of various cancerous or transformed cells. Oral or intra-peritoneal administration of resveratrol decreases expressions of COX-1, COX-2, and PGE2 reducing the number and size of esophageal tumors in N-nitrosomethylbenzylamine-induce rat tumor model [181] . Similarly, oral administration of resveratrol limits the formation of aberrant crypt foci and tumors in the colon of rats that are treated with chemical carcinogen, i.e., 1,2-dimethylhydrazine (DMH) or azoxymethane.…”

Resveratrol Exerts Differential Effects in Vitro and in Vivo against Ovarian Cancer Cells

“…Resveratrol is gaining tremendous importance as it possesses cancer preventive as well as anticancer activities in various biological systems (reviewed by Bishayee, 2009). In animal studies, resveratrol prevents or delays the development of skin (Jang et al, 1997), mammary (Banerjee et al, 2002) and prostate (Harper et al, 2007) tumors as well as blocks or suppresses esophageal (Li et al, 2002), gastric (Zhou et al, 2005), small intestinal (Schneider et al, 2001), colonic (Tessitore at al., 2000;Sengottuvelan et al, 2006) pancreatic (Harikumar et al, 2010), and hepatic (Bishayee & Dhir, 2009) tumorigenesis. Resveratrol has also been shown to possess in vitro cytotoxic effects against a wide variety of human tumor cells, including lymphoid and myeloid cancer cells as well as skin, breast, ovary, cervix, prostate, stomach, colon, pancreas, liver and thyroid carcinoma cells (reviewed by Aggarwal et al, 2004;Kundu and Surh, 2008).…”

Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′‐tetramethoxystilbene (DMU‐212) on adenoma development in the ApcMin+ mouse and cyclooxygenase‐2 in human‐derived colon cancer cells

“…[15][16][17][18][19][20][21][22][23] These findings characterize COX enzymes as potentially important targets of stilbenes. COX-1 and COX-2 catalyze the conversion of arachidonic acid to protumorigenic eicasonoids, such as prostaglandin E-2 (PGE-2), which are involved in the maintenance of the malignant phenotype.…”