Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines
Comparative analysis of the effects of flavonoids on proliferation, cytotoxicity, and apoptosis in human colon cancer cell lines
复制标题
DOI：
10.1007/s003940050054
复制
发表时间：
1999-06-01
影响因子：
5
通讯作者：
Daniel, H
中科院分区：
文献类型：
--
作者：
Kuntz, S;Wenzel, U;Daniel, H
黄酮类化合物是多酚类化合物，普遍存在于植物源性食品中。由于肠上皮细胞直接暴露于这些饮食成分，它们在肿瘤发展中的保护作用可能占上风，特别是在肠道中。我们已经筛选了超过30种黄酮类化合物对人结肠癌细胞系Caco-2（显示小肠上皮细胞的特征）和HT-29（类似于结肠隐窝细胞）中细胞增殖和潜在细胞毒性的影响。此外，对于选定的化合物，我们通过测定半胱天冬酶-3活化来评估它们是否诱导细胞凋亡。对类黄酮的剂量依赖性作用的研究显示所有化合物的抗增殖活性，其EC 50值范围在39.7 +/- 2.3 μ M（黄芩素）和203.6 +/- 15.5 μ M（地奥司明）之间。在几乎所有的情况下，生长抑制类黄酮发生在细胞毒性的情况下。无论是基于亚类（即，在一个子集的实验中，我们检查了最有效的化合物的抗增殖活性的每个黄酮类化合物亚组，除了在LLC-PK 1，肾小管细胞系，和人乳腺癌细胞系MCF-7。在四个黄酮醇测试，三个显示几乎相同的抗增殖活性在所有细胞系，但非瑟酮在MCF-7细胞中的效力较低。黄烷酮bavachinin和黄烷酮抑制Caco-2和MT-29细胞的生长，其EC 50值低于LLC-PK 1和MCF-7细胞中获得的EC 50值。LLC-PK 1和MCF-7细胞对生长停滞的较低敏感性在黄酮黄芩素的情况下甚至更明显。LLC-PK 1和MCF-7中的半数最大生长抑制需要比肠细胞系中所需浓度高2.5和6.6倍的浓度。黄酮类化合物对LLC-PK 1和MCF-7细胞的凋亡无影响，而黄芩素和杨梅苷对HT-29和Caco-2细胞的凋亡有诱导作用。黄酮类化合物的生长抑制和诱导细胞凋亡的能力不能根据其化学组成和结构来预测。
Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Their proposed protective role in tumor development may prevail especially in the intestinal tract due to direct exposure of intestinal epithelia to these dietary ingredients. We have screened more than 30 flavonoids for their effects on cell proliferation and potential cytotoxicity in the human colon cancer cell lines Caco-2, displaying features of small intestinal epithelial cells, and HT-29, resembling colonic crypt cells. In addition, for selected compounds we assessed whether they induce apoptosis by determining caspase-3 activation. Studies on the dose dependent effects of the flavonoids showed antiproliferative activity of all compounds with EC50 values ranging between 39.7 +/- 2.3 mu M (baicalein) and 203.6 +/- 15.5 mu M (diosmin). In almost all cases, growth inhibition by the flavonoids occured in the absence of cytotoxicity. There was no obvious structure-activity relationship in the antiproliferative effects either on basis of the subclasses (i.e., isoflavones, flavones, flavonols, flavanones) or with respect to kind or position of substituents within a class.In a subset of experiments we examined the antiproliferative activities of the most potent compound of each flavonoid subgroup in addition in LLC-PK1, a renal tubular cell line, and the human breast cancer cell line MCF-7. Out of four flavonols tested, three displayed almost equal antiproliferative activities in all cell lines but fisetin was less potent in MCF-7 cells. The flavanones bavachinin and flavanone inhibited growth of Caco-2 and MT-29 cells with lower EC50 values than that obtained in LLC-PK1 and MCF-7 cells. The lower susceptibility of LLC-PK1 and MCF-7 cells towards growth arrest was even more pronounced in the case of the flavone baicalein, Half maximal growth-inhibition in LLC-PK1 and MCF-7 required 2.5 and 6.6 fold higher concentrations than that needed in the intestinal cell lines. The flavonoids failed to affect apoptosis in LLC-PK1 and MCF-7, whereas baicalein and myricetin were able to induce apoptosis in HT-29 and Caco-2 cells.In conclusion, flavonoids of the flavone, flavonol, flavanone, and isoflavone classes possess antiproliferative effects in different cancer cell lines. The capability of flavonoids for growth inhibition and induction of apoptosis can not be predicted on the basis of their chemical composition and structure.