Pro-inflammatory cytokines such as TNF-alpha play an important role in the pathophysiology of diseases such as Crohn's and ulcerative colitis which cause increased risk of colorectal cancer. However, the mechanisms underlying colon carcinogenesis are not well understood. Herein we report that inhibition/antisense abolition of polyol pathway enzyme, aldose reductase (AR) inhibited the TNF-alpha-induced synthesis of prostaglandin E2 and the activity of cyclooxygenase (Cox) in human colon cancer cells, Caco-2. Inhibition of AR prevented TNF-alpha-induced activation of PKC and NF-kappaB which resulted in the abrogation of Cox-2 mRNA and protein expression. These results suggest that inhibition of AR could be a novel chemopreventive approach to colon cancer.