Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′-tetramethoxystilbene (DMU-212) on adenoma development in the ApcMin+ mouse and cyclooxygenase-2 in human-derived colon cancer cells
Comparison of the effects of the chemopreventive agent resveratrol and its synthetic analog trans 3,4,5,4′-tetramethoxystilbene (DMU-212) on adenoma development in the ApcMin+ mouse and cyclooxygenase-2 in human-derived colon cancer cells
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DOI：
10.1002/ijc.20884
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发表时间：
2005-06-10
影响因子：
6.4
通讯作者：
Gescher, AJ
中科院分区：
文献类型：
--
作者：
Sale, S;Tunstall, RG;Gescher, AJ
天然存在的具有癌症化学预防特性的分子，如植物抗毒素白藜芦醇(3，5，4‘-三羟基二苯乙烯)是指导设计具有更好药理特性的新型药物的先导分子。合成的白藜芦醇类似物3，4，5，4‘-四甲氧基二苯乙烯(DMU-212)对人结肠癌细胞具有比白藜芦醇更强的抗增殖作用。我们测试了DMU-212在APC(Min+)小鼠体内对腺瘤发展的更有效抑制作用的假设，APC(Min+)小鼠是一种人类肠癌发生的模型。APC(Min+)小鼠在饲料中加入二苯乙烯类化合物(0.2%)，实验结束后计数腺瘤。与未经治疗的对照组相比，白藜芦醇和DMU-212分别减少了27%和24%的腺瘤负荷。环氧合酶(COX)酶是白藜芦醇的重要作用靶点，我们研究了DMU-212是否干扰COX在人结肠细胞中的表达和活性。Hca-7癌细胞与二苯乙烯衍生物(1-50 PM)孵育24-96小时可减少前列腺素E-2(PGE-2)的产生，但只有白藜芦醇可降低COX-2蛋白的表达。在饮食中服用二苯乙烯衍生物(0.2%)3周的小鼠中，与对照组相比，肠道粘膜中的PGE-2水平降低了45%到62%。白藜芦醇抑制纯化的COX制剂中的酶活性，而DMU-212不能这样做。DMU-212在细胞内和体内的PGE-2降低可能是通过其代谢产物介导的。这些结果表明，白藜芦醇分子产生DMU-212的改变并不会消除其减少APC(Min+)小鼠腺瘤数量或干扰细胞中PGE-2产生的能力。(C)2005年Wiley-Liss，Inc.
Naturally occurring molecules with putative cancer chemopreventive properties such as the phytoalexin resveratrol (3,5,4'-trihydroxystilbene) are lead molecules that guide the design of novel agents with improved pharmacologic properties. The synthetic resveratrol analog 3,4,5,4'-tetramethoxvstilbene (DMU-212) has been shown to possess stronger antiproliferative properties in human colon cancer cells than resveratrol. We tested the hypothesis that DMU- 212 is also a more potent inhibitor of adenoma development in the Apc(Min+) mouse, a model of human intestinal carcinogenesis. Apc(Min+) mice received either stilbene derivative with the diet (0.2%), and adenomas were counted after experiments were terminated. Resveratrol and DMU-212 decreased adenoma load by 27% and 24%, respectively, compared to untreated controls. Cyclooxyenase (COX) enzymes are important mechanistic targets of resveratrol, and we investigated whether DMU-212 interferes with the expression and activity of COX in human colon cells. Incubation of HCA-7 cancer cells for 24-96 hr with either stilbene derivative (1-50 PM) decreased prostaglandin E-2 (PGE-2) production, but only resveratrol decreased COX-2 protein expression. In mice, which received either stilbene derivative (0.2%) for 3 weeks with their diet, PGE-2 levels in the intestinal mucosa were reduced by between 45% and 62% compared to mice on control diet. While resveratrol inhibited enzyme activity in purified COX preparations, DMU-212 failed to do so. The PGE-2 decrease seen with DMU-212 in cells and in vivo is probably mediated via its metabolites. The results suggest that alteration of the resveratrol molecule to generate DMU-212 does not abrogate its ability to decrease adenoma number in Apc(Min+) mice or to interfere with PGE-2 generation in cells. (c) 2005 Wiley-Liss, Inc.