phenylethyl-3-methylcaffeate and Colonic-Neoplasms

Recent evidence supports the theory that tumor growth in vivo depends on evasion of normal homeostatic control mechanisms that operate through induction of cell death by apoptosis. This study tested the hypothesis that several potential chemopreventive agents share the ability to induce apoptosis and that inhibition of apoptosis is a mechanism of tumor 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-phenylhexyl isothiocyanate (PHITC) that were observed in our previous studies are associated with the induction or inhibition of apoptosis in azoxymethane (AOM)-induced colon tumors in male F344 rats. At 5 weeks of age, groups of rats were fed control (modified AIN-76A) diet or diets containing 320 ppm of sulindac, 2000 ppm of curcumin, 750 ppm of PEMC, or 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 weight) once weekly for 2 weeks. To study the effect of sulindac administered during promotion/progression stage, the rats were fed the control diet initially and then fed the experimental diet containing 320 ppm of sulindac 14 weeks after the second AOM treatment. The rats were sacrificed 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, curcumin, 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 indices in the control, sulindac, curcumin, and PEMC diets were 8.3, 17.6, 17.7, and 18.5%, respectively, and in sulindac administered during promotion/progression stage, the apoptotic index was 19.1%. However, dietary 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 the degree of apoptosis. Therefore apoptosis seems to be a reliable biomarker for the evaluation of potential agents for cancer prevention.

Topics: Adenocarcinoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Apoptosis; Azoxymethane; Biomarkers, Tumor; Caffeic Acids; Carcinogens; Colonic Neoplasms; Curcumin; Isothiocyanates; Male; Rats; Rats, Inbred F344; Sulindac

Previous studies from this laboratory have established that caffeic acid esters present in propolis, a natural resin produced by honey bees, are potent inhibitors of human colon adenocarcinoma cell growth, carcinogen-induced biochemical changes, and preneoplastic lesions in the rat colon. The present study was designed to investigate the chemopreventive action of dietary phenylethyl-3-methylcaffeate (PEMC) on azoxymethane-induced colon carcinogenesis and to examine the modulating effect of PEMC on phosphatidylinositol-specific phospholipase C (PI-PLC), phospholipase A2, lipoxygenase (LOX), and cyclooxygenase activities in the colonic mucosa and tumor tissues in male F344 rats. At 5 weeks of age, groups of rats were fed the control (modified AIN-76A) diet, or a diet containing 750 ppm of PEMC. At 7 weeks of age, all animals except those in the vehicle (normal saline)-treated groups were given 2 weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. All groups were maintained on their respective dietary regimen until the termination of the experiment 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Both colonic mucosa and tumors were analyzed for PI-PLC, phospholipase A2, cyclooxygenase, and LOX activities. The results indicate that dietary administration of PEMC significantly inhibited the incidence and multiplicity of invasive, noninvasive, and total (invasive plus noninvasive) adenocarcinomas of the colon (P < 0.05-0.004). Dietary PEMC also suppressed the colon tumor volume by 43% compared to the control diet. Animals fed the PEMC diet showed significantly decreased activities of colonic mucosal and tumor PI-PLC (about 50%), but PEMC diet had no effect on phospholipase A2. The production of 5(S)-, 8(S)-, 12(S)-, and 15(S)-hydroxyeicosatetraenoic acids via the LOX pathway from arachidonic acid was reduced in colonic mucosa and tumors (30-60%) of animals fed the PEMC diet as compared to control diet. PEMC had no effect on the formation of colonic mucosal cyclooxygenase metabolites but inhibited the formation in colonic tumors by 15-30%. The precise mechanism by which PEMC inhibits colon tumorigenesis remains to be elucidated. It is likely that the chemopreventive action may be related, at least in part, to the modulation of PI-PLC-dependent signal transduction and LOX-mediated arachidonic acid metabolism.

Topics: Animals; Anticarcinogenic Agents; Azoxymethane; Body Weight; Caffeic Acids; Colon; Colonic Neoplasms; Evaluation Studies as Topic; Intestinal Mucosa; Lipoxygenase; Male; Phosphatidylinositol Diacylglycerol-Lyase; Phosphoinositide Phospholipase C; Phospholipases A; Phospholipases A2; Phosphoric Diester Hydrolases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred F344