MODULATION OF APOPTOSIS BY SULINDAC, CURCUMIN, PHENYLETHYL-3-METHYLCAFFEATE, AND 6-PHENYLHEXYL ISOTHIOCYANATE - APOPTOTIC INDEX AS A BIOMARKER IN COLON-CANCER CHEMOPREVENTION AND PROMOTION

Recent evidence supports the theory that tumor growth in vivo depends on evasion of normal homeostatic control mechanisms that operate throu gh induction of cell death by apoptosis, This study tested the hypothe sis that several potential chemopreventive agents share the ability to induce apoptosis and that inhibition of apoptosis is a mechanism of t umor promoters. The present study was designed to investigate whether the chemopreventive properties of sulindac, curcumin, and phenylethyl- 3-methylcaffeate (PEMC) and the tumor-promoting activity of 6-phenyl-h exyl isothiocyanate (PHITC) that were observed in our previous studies are associated with the induction or inhibition of apoptosis in azoxy methane (AOM)-induced colon tumors in male F344 rats, At 5 weeks of ag e, groups of rats were fed control (modified AIN-76A) diet or diets co ntaining 320 ppm of sulindac, 2000 ppm of curcumin, 750 ppm of PEMC, o r 640 ppm of PHITC, At 7 weeks of age, all rats except those intended for vehicle (normal saline) treatment were given AOM (15 mg/kg body we ight) once weekly for 2 weeks, To study the effect of sulindac adminis tered during promotion/progression stage, the rats were fed the contro l diet initially and then fed the experimental diet containing 320 ppm of sulindac 14 weeks after the second AOM treatment, The rats were sa crificed 52 weeks after carcinogen treatment, and their colonic tumors were subjected to histopathological evaluation and the appearance of apoptosis, In the current study, chronic administration of sulindac, c urcumin, and PEMC or sulindac given only during promotion/progression significantly increased the apoptotic index (percentage of apoptosis) as compared to administration of the control diet; the apoptotic indic es in the control, sulindac, curcumin, and PEMC diets were 8.3, 17.6, 17.7, and 18.5%, respectively, and in sulindac administered during pro motion/progression stage, the apoptotic index was 19.1%, However, diet ary PHITC blocked the process of apoptosis during colon carcinogenesis , The apoptotic index in PHITC diet was 7.0%, Taken together, our data show that chemopreventive properties of agents are correlated with th e degree of apoptosis, Therefore apoptosis seems to be a reliable biom arker for the evaluation of potential agents for cancer prevention.