Chemoprevention of 1,2-Dimethylhydrazine-Induced Colon Carcinogenesis by a Non-Steroidal Anti-Inflammatory Drug, Etoricoxib, in Rats: Inhibition of Nuclear Factor kB

Abstract

Etoricoxib, a highly selective cyclooxygenase- 2 (COX-2) inhibitor (a non steroidal anti-inflammatory drug)used for the treatment of rheumatoid arthritis and osteoarthritis, has been newly marketed and studied for thechemopreventive response in the 1,2-dimethylhydrazine dihydrochloride (DMH) induced rat colon cancer model.Male Sprague-Dawley rats were divided into four groups. Group I served as the Control and received thevehicle treatment, while Groups 2 and 3 were administered freshly prepared DMH (30 mg/kg body weight,subcutaneously) in 1mM EDTA-saline (pH 7.0). Groups 3 and 4 received Etoricoxib (0.64 mg/kg body weight,orally) daily prepared in 0.5% carboxymethyl cellulose. After a 6 week treatment period, animals were sacrificedand the colons were subjected to macroscopic and histopathological studies. Well characterized pre-neoplasticfeatures such as multiple plaque lesions (MPLs), aberrant crypts (ACs) and aberrant crypt foci (ACF) werefound in the DMH group. The number was reduced in DMH + Etoricoxib group, while very few MPLs andACFs were recorded in the Etoricoxib only group. Also, histologically well characterized dysplasia and hyperplasiawere observed in DMH treated group. The simultaneous administration of DMH and Etoricoxib reduced thesefeatures. To study apoptosis, colonocytes were isolated by metal chelation from colonic sacs and studied byfluorescent staining. The DMH treated animals produced much less apoptotic nuclei as compared to the Control.The number of apoptotic nuclei was also found higher in the DMH + Etoricoxib group as well as in Etoricoxibonly group. Studies of a nuclear transcription factor (NF-κB) and COX-2 by Western blot analysis andimmunohistochemistry demonstrated expression of both to be elevated in the DMH treated group but reducedin the DMH + Etoricoxib group. Expression was also low in the Etoricoxib only group. It may be concluded thatthe drug, Etoricoxib, has the potential to reduce DMH induced colon cancer development.