Prevention of colon cancer by low doses of celecoxib, a cyclooxygenase inhibitor, administered in diet rich in omega-3 polyunsaturated fatty acids.
Epidemiologic and animal studies suggest that a high-fat diet containing mixed lipids promotes colorectal cancer, whereas fish oil lacks promoting effect. Although cyclooxygenase-2 (COX-2) inhibitors are effective chemopreventive agents against colon carcinogenesis, administration of high doses of these agents over time may induce side effects. Here, we compared the efficacy of moderately high and low doses of celecoxib administered in diets high in mixed lipids (HFML) or fish oil (HFFO) against azoxymethane-induced colon carcinogenesis in male F344 rats. One day after the last azoxymethane treatment (15 mg/kg body weight once weekly for 2 weeks), groups of rats were fed the HFML and HFFO diets containing 0, 250, 500, and 1,000 ppm celecoxib. Rats were killed 26 weeks later and colon tumors were subjected to histopathologic examination and analyzed for total COX and COX-2 synthetic activities and COX-2 expression. Rats fed the HFFO diet showed significantly lower colon tumor incidence and multiplicity compared with rats fed the HFML diet. Celecoxib at 250, 500, and 1,000 ppm in either diet significantly suppressed colon carcinogenesis. Inhibition of colon adenocarcinomas were more pronounced in animals given 250 ppm celecoxib in HFFO diet compared with 250 ppm celecoxib given in HFML diet, suggesting some synergism between omega-3 polyunsaturated fatty acids (PUFA) and celecoxib. Inhibition of colon tumors by celecoxib was associated with lower levels of COX-2 activity and expression in colon tumors. These studies support the use of low doses of celecoxib in omega-3 PUFA-rich diet as a promising approach for clinical trials.
Reddy
Bandaru S
BS
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers State University of New Jersey, Piscataway, New Jersey 08854, USA. breddy@rci.rutgers.edu
Patlolla
Jagan M
JM
Simi
Barbara
B
Wang
S H
SH
Rao
Chinthalapally V
CV
D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D000068579:Celecoxib; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004032:Diet; D004305:Dose-Response Relationship, Drug; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D013449:Sulfonamides / Q000008:administration & dosage*
D002273:Carcinogens; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D015525:Fatty Acids, Omega-3; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D001397:Azoxymethane