Rao C V, Desai D, Simi B, Kulkarni N, Amin S, Reddy B S
Division of Nutritional Carcinogenesis, American Health Foundation, Valhalla, New York 10595.
Cancer Res. 1993 Sep 15;53(18):4182-8.
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.
本实验室之前的研究表明，蜜蜂蜂巢蜂胶中含有的咖啡酸酯是人类结肠肿瘤细胞生长的有效抑制剂，这表明这些化合物可能对结肠癌发生具有抗肿瘤活性。本研究旨在调查：(a) 咖啡酸甲酯 (MC) 和咖啡酸苯乙酯 (PEC) 对雄性F344大鼠肝脏和结肠黏膜中由氧化偶氮甲烷 (AOM) 诱导的鸟氨酸脱羧酶 (ODC)、酪氨酸蛋白激酶 (TPK) 和花生四烯酸代谢的抑制作用；(b) 咖啡酸、MC、PEC、3-甲基咖啡酸苯乙酯 (PEMC) 和二甲基咖啡酸苯乙酯 (PEDMC) 对肝脏和结肠黏膜体外花生四烯酸代谢的影响；(c) PEC、PEMC和PEDMC对F344大鼠结肠中AOM诱导的异常隐窝灶 (ACF) 形成的影响。5周龄时，给动物分组喂食含600 ppm MC或PEC的饲料（生化研究）或含500 ppm PEC、PEMC或PEDMC的饲料（ACF研究）。两周后，除溶剂处理组外，所有动物均皮下注射AOM，每周1次，共2周。用于生化研究的动物在5天后处死，分析结肠黏膜和肝脏中的ODC、TPK、脂氧合酶和环氧化酶代谢产物。用于ACF研究的动物在9周后处死，分析结肠中的ACF。结果表明，PEC饲料显著抑制肝脏和结肠中AOM诱导的ODC（P < 0.05）和TPK（P < 0.001）活性。PEC饲料显著（P < 0.001）抑制AOM诱导的脂氧合酶代谢产物8(S)-和12(S)-羟基二十碳四烯酸（HETE）。喂食MC饲料的动物对ODC以及5(S)-、8(S)-和12(S)-HETE表现出中度抑制作用，对结肠TPK活性有显著（P < 0.001）影响。然而，MC和PEC饲料对环氧化酶代谢无显著抑制作用。在体外研究中，咖啡酸和MC仅在100 microM浓度时对HETE形成有抑制作用，而PEC、PEMC和PEDMC以剂量依赖方式抑制体外HETE形成。喂食PEC（55%）、PEMC（82%）或PEDMC（81%）的动物中，AOM诱导的结肠ACF受到显著抑制。本研究结果表明，蜂蜜中含有的PEC、PEMC和PEDMC可抑制AOM诱导的结肠癌前病变、ODC、TPK和脂氧合酶活性，这些均与结肠癌发生相关。
