Previous work from this laboratory established that
caffeic acid esters, present in the
propolis of honey bee
hives, are potent inhibitors of human colon
tumor cell growth, suggesting that these compounds may possess antitumor activity against colon
carcinogenesis. The present study was designed to investigate (a) the inhibitory effects of
methyl caffeate (MC) and phenylethyl caffeate (PEC) on
azoxymethane (AOM)-induced
ornithine decarboxylase (ODC),
tyrosine protein kinase (TPK), and
arachidonic acid metabolism in liver and colonic mucosa of male F344 rats, (b) the effects of
caffeic acid, MC, PEC, phenylethyl-3-methylcaffeate (PEMC), and phenylethyl dimethylcaffeate (PEDMC) on in vitro
arachidonic acid metabolism in liver and colonic mucosa, and (c) the effects of PEC, PEMC, and PEDMC on AOM-induced
aberrant crypt foci (ACF) formation in the colon of F344 rats. At 5 weeks of age, groups of animals were fed diets containing 600 ppm MC or PEC (biochemical study) or 500 ppm PEC, PEMC, or PEDMC (ACF study). Two weeks later, all animals except the vehicle-treated groups were given s.c.
injections of AOM, once weekly for 2 weeks. The animals intended for the biochemical study were sacrificed 5 days later and colonic mucosa and liver were analyzed for ODC, TPK,
lipoxygenase, and
cyclooxygenase metabolites. The animals intended for the ACF study were sacrificed 9 weeks later and analyzed for ACF in the colon. The results indicate that the PEC diet significantly inhibited AOM-induced ODC (P < 0.05) and TPK (P < 0.001) activities in liver and colon. The PEC diet significantly (P < 0.001) suppressed the AOM-induced
lipoxygenase metabolites 8(S)- and 12(S)-hydroxyeicosatetraenoic
acid (
HETE). The animals fed the MC diet exhibited a moderate inhibitory effect on ODC and 5(S)-, 8(S)-, 12(S)-, and 15(S)-HETEs and a significant (P < 0.001) effect on colonic TPK activity. However, the MC and PEC diets showed no significant inhibitory effects on
cyclooxygenase metabolism. In an in vitro study,
caffeic acid and MC showed inhibitory effects on
HETE formation only at a 100 microM concentration, whereas PEC, PEMC, and PEDMC suppressed in vitro
HETE formation in a dose-dependent manner. AOM-induced colonic ACF were significantly inhibited in the animals fed PEC (55%), PEMC (82%), or PEDMC (81%). The results of the present study indicate that PEC, PEMC, and PEDMC, present in honey, inhibit AOM-induced colonic preneoplastic lesions, ODC, TPK, and
lipoxygenase activity, which are relevant to colon
carcinogenesis.