Differential modulation of cyclooxygenase-mediated prostaglandin production by the putative cancer chemopreventive flavonoids tricin, apigenin and quercetin
Differential modulation of cyclooxygenase-mediated prostaglandin production by the putative cancer chemopreventive flavonoids tricin, apigenin and quercetin
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DOI：
10.1007/s00280-006-0228-3
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发表时间：
2006-12-01
影响因子：
3
通讯作者：
Gescher, Andreas J.
中科院分区：
文献类型：
--
作者：
Al-Fayez, Mohammad;Cai, Hong;Gescher, Andreas J.
目的：饮食来源的黄酮类化合物在临床前模型中具有癌症化学预防特性。大多数类黄酮的药理学知识不足以保证其进入临床评估。方法：这里比较了来自米糠的三种黄酮类化合物三辛、来自叶类蔬菜的芹菜素以及来自洋葱和苹果的槲皮素调节环氧合酶（COX-）催化前列腺素 E-2（PGE-2）生成的能力。具体来说，研究了它们对以下参数的影响：（1）COX酶活性，（2）人源性结肠癌细胞HCA-7中的COX-2表达，其组成型表达COX-2，（3）佛波酯介导的人结肠上皮细胞（HCEC）中的COX-2诱导，以及（4）细胞培养中的PGE-2水平。结果：Tricin 和槲皮素抑制纯化的 COX-1 和 -2 制剂中的酶活性，IC50 值接近 1（tricin）和 5 muM（槲皮素）。芹菜素浓度高达 25 μM 时不会影响 COX 酶活性。将类黄酮与细胞一起孵育 6 或 24 小时，并分别通过蛋白质印迹和竞争性免疫测定评估 COX-2 蛋白表达和 PGE-2 水平。这些药物均不影响 HCA-7 细胞中 COX-2 的组成型表达。孵育 6 小时后，芹菜素（而非三辛或槲皮素）下调 HCEC 细胞中诱导型 COX-2 的表达。所有三种类黄酮均降低了两个时间点的 HCA-7 细胞上清液中以及 6 小时时的 HCEC 细胞上清液中 PGE-2 的细胞水平。结论：结果表明，这些结构相似的黄酮类化合物以不同的方式调节 COX 介导的 PGE-2 产生。它们降低前列腺素水平的能力可能有助于其癌症化学预防功效。
Objectives: Diet-derived flavonoids possess cancer chemopreventive properties in preclinical models. The knowledge of the pharmacology of most flavonoids is insufficient to warrant their advancement to clinical evaluation. Methods: Here the three flavonoids tricin from rice bran, apigenin from leafy vegetables, and quercetin from onions and apples, were compared in terms of their ability to modulate cyclooxygenase- (COX-) catalyzed prostaglandin E-2 (PGE-2) generation. Specifically their effects on the following parameters were studied: (1) COX enzyme activity, (2) COX-2 expression in human-derived colon cancer cells HCA-7, which express COX-2 constitutively, (3) phorbol ester-mediated COX-2 induction in human colon epithelial cells (HCEC), and (4) PGE-2 levels in cellular incubations. Results: Tricin and quercetin inhibited enzyme activity in purified COX-1 and -2 preparations with IC50 values of near 1 (tricin) and 5 mu M (quercetin). Apigenin at up to 25 mu M did not affect COX enzyme activity. Flavonoids were incubated with cells for 6 or 24 h and COX-2 protein expression and PGE-2 levels were assessed by Western blot and competitive immunoassay, respectively. None of the agents affected constitutive COX-2 expression in HCA-7 cells. Apigenin, but not tricin or quercetin, down-regulated inducible COX-2 expression in HCEC cells on 6 h incubation. All three flavonoids reduced cellular levels of PGE-2 in the supernatant of HCA-7 cells at both time points and of HCEC cells at 6 h. Conclusions: The results demonstrate that these structurally similar flavonoids regulate COX-mediated PGE-2 production in different fashions. Their ability to attenuate prostanoid levels may contribute to their cancer chemopreventive efficacy.