CHEMOPREVENTION OF COLON CARCINOGENESIS BY DIETARY CURCUMIN, A NATURALLY-OCCURRING PLANT PHENOLIC COMPOUND

Human epidemiological and laboratory animal model studies have suggest ed that nonsteroidal antiinflammatory drugs reduce the risk of develop ment of colon cancer and that the inhibition of colon carcinogenesis i s mediated through the alteration in cyclooxygenase metabolism of arac hidonic acid. Curcumin, which is a naturally occurring compound is pre sent in turmeric, possesses both antiinflammatory and antioxidant prop erties, and has been tested for its chemopreventive properties in skin and forestomach carcinogenesis. The present study was designed to inv estigate the chemopreventive action of dietary curcumin on azoxymethan e-induced colon carcinogenesis and also the modulating effect of this agent on the colonic mucosal and tumor phospholipase A(2), phospholipa se C gamma 1, lipoxygenase, and cyclooxygenase activities in male F344 rats, At 5 weeks of age, groups of animals were fed the control (modi fied AIN-76A) diet or a diet containing 2000 ppm of curcumin. At 7 wee ks of age, all animals, except those in the vehicle (normal saline)-tr eated groups, were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight. An groups were continued on thei r respective dietary regimen until the termination of the experiment a t 52 weeks after the carcinogen treatment. Colonic tumors were evaluat ed histopathologically. Colonic mucosa and tumors were analyzed for ph ospholipase A(2), phospholipase C gamma 1, ex vivo prostaglandin (PG) E(2), cyclooxygenase, and lipoxygenase activities. The results indicat e that dietary administration of curcumin significantly inhibited inci dence of colon adenocarcinomas (P < 0.004) and the multiplicity of inv asive (P < 0.015), noninvasive (P < 0.01), and total (invasive plus no ninvasive) adenocarcinomas (P < 0.001). Dietary curcumin also signific antly suppressed the colon tumor volume by >57% compared to the contro l diet. Animals fed the curcumin diet showed decreased activities of c olonic mucosal and tumor phospholipase A(2) (50%) and phospholipase C gamma 1 (40%) and levels of PGE(2), (>38%). The formation of prostagla ndins such as PGE(2), PGF(2 alpha), PGD(2), 6-keto PGF(1 alpha), and t hromboxane B-2 through the cyclooxygenase system and production of 5(S )-, 8(S)-, 12(S)-, and 15(S) hydroxyeicosatetraenoic acids via the Lip oxygenase pathway from arachidonic acid were reduced in colonic mucosa and tumors of animals fed the curcumin diet as compared to control di et. Although the precise mechanism by which curcumin inhibits colon tu morigenesis remains to be elucidated, it is likely that the chemopreve ntive action, at least in part, may be related to the modulation of ar achidonic acid metabolism.