Differential inhibitory effects of the polyphenol ellagic acid on inflammatory mediators NF-kappaB, iNOS, COX-2, TNF-alpha, and IL-6 in 1,2-dimethylhydrazine-induced rat colon carcinogenesis

Abstract

Dietary polyphenols have been found to possess preventive and therapeutic potential against several types of cancers. We investigated the effect of ellagic acid on colon cancer induced by 1,2-dimethylhydrazine in rats. Male Wistar albino rats were divided into four groups. Group 1 served as control, group 2 rats received ellagic acid 60 mg/kg bodyweight/every day p.o. throughout the experiment. Rats from groups 3 and 4 were given subcutaneous (s.c.) injections of 1,2-dimethylhydrazine (20 mg/kg body weight) once a week for the first 15 weeks; rats in group 4 received ellagic acid as in group 2 after the last injection of 1,2-dimethylhydrazine and continued till the end of the experimental period of 30 weeks. 1,2-dimethylhydrazine-induced rats exhibited alterations in cancer tumour markers [5'-nucleotidase (5'-ND), gamma glutamyl transpeptidase (gamma-GT), carcinoembryonic antigen (CEA), alphafetoprotein (AFP) and cathepsin-D (CD)]; pathophysiological markers [alkaline phosphatase (ALP) and lactate dehydrogenase (LDH)] and oral administration of ellagic acid restored the levels of these marker enzymes. Nuclear factor-kappa B (NF-kappaB) actively involved in the regulation of both pro-inflammatory proteins [inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2)] and pro-inflammatory cytokines [tumour necrosis factor (TNF)-alpha and interleukin (IL)-6] and in our study 1,2-dimethylhydrazine-induced group exhibited elevated expressions of all these inflammatory proteins. Ellagic acid administration reduced the expressions of NF-kappaB, COX-2, iNOS, TNF-alpha and IL-6 as confirmed by immunohistochemical, immunoblot and immunofluorescence analysis during 1,2-dimethylhydrazine-induced colon carcinogenesis. In conclusion, ellagic acid demonstrates anti-inflammatory property by iNOS, COX-2, TNF-alpha and IL-6 down-regulation due to inhibition of NF-kappaB and exerts its chemopreventive effect on colon carcinogenesis.