Chemopreventive effects of NSAIDs on cytokines and transcription factors during the early stages of colorectal cancer

The earliest stages of colorectal cancer have been linked to inflammatory responses caused by carcinogens,but the molecular signaling of various pro- and anti-inflammatory cytokines and transcription factors in colorectal cancer remains unknown. the higher expression and secretion of various pro-inflammatory cytokines and their autocrine and paracrine functions play an important role in the activation of transcription factors,which in turn promote tumorigenesis. nf-κb serves as a vital biomolecule that transcribes a number of pro-inflammatory cytokines and anti-apoptotic proteins. pro-inflammatory cytokines can also activate jak3/stat3 signaling pathways,thereby increasing inflammation and cell survival. in the present study,the expression of il-1β,il-2,il-4,ifnγ,tnf-α,inos,cox-2,jak3,stat3 and nf-κb were increased in the early stages of experimental colorectal cancer. the increased expression of these inflammatory molecules was reversed by the simultaneous administration of non-steroidal anti-inflammatory drugs (nsaids; sulindac and celecoxib). the anti-inflammatory activity of the nsaids was found to be mediated by the inhibition of nf-κb (p65) dna-binding activity. the anti-neoplastic end effect of the nsaids in the isolated colonocytes was demonstrated by an increased level of apoptosis. this study suggests that nsaids inhibit nf-κb and jak3/stat3 signaling and down-regulate pro-inflammatory cytokines to a level that inhibits inflammation and carcinogenesis. copyright © 2011 by institute od pharmacology polish academy of sciences.