Kuntz S, Wenzel U, Daniel H
Institute of Nutritional Sciences, Freising-Weihenstephan, Germany.
Eur J Nutr. 1999 Jun;38(3):133-42. doi: 10.1007/s003940050054.
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 microM (baicalein) and 203.6 +/- 15.5 microM (diosmin). In almost all cases, growth inhibition by the flavonoids occurred 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, flavonones) 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 HT-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.
黄酮类化合物是普遍存在于植物性食物中的多酚类化合物。它们在肿瘤发展中所提出的保护作用可能尤为突出，特别是在肠道中，因为肠道上皮细胞会直接接触这些膳食成分。我们已筛选了30多种黄酮类化合物，研究它们对人结肠癌细胞系Caco-2（具有小肠上皮细胞特征）和HT-29（类似于结肠隐窝细胞）的细胞增殖及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的激活情况来评估它们是否诱导细胞凋亡。黄酮类化合物的剂量依赖性效应研究表明，所有化合物均具有抗增殖活性，其半数有效浓度（EC50）值介于39.7±2.3微摩尔（黄芩素）和203.6±15.5微摩尔（地奥司明）之间。几乎在所有情况下，黄酮类化合物的生长抑制作用均在无细胞毒性的情况下发生。无论是基于亚类（即异黄酮、黄酮、黄酮醇、黄烷酮），还是就某一类中取代基的种类或位置而言，其抗增殖效应均不存在明显的构效关系。在一组实验中，我们还检测了每个黄酮类亚组中最有效的化合物对肾小管细胞系LLC-PK1和人乳腺癌细胞系MCF-7的抗增殖活性。在所测试的四种黄酮醇中，有三种在所有细胞系中表现出几乎相同的抗增殖活性，但漆黄素在MCF-7细胞中的活性较低。黄烷酮毛鱼藤酮和黄烷酮抑制Caco-2和HT-29细胞生长的EC50值低于其在LLC-PK1和MCF-7细胞中的值。黄酮类化合物黄芩素对LLC-PK1和MCF-7细胞生长抑制的敏感性更低，在LLC-PK1和MCF-7细胞中产生半数最大生长抑制所需的浓度分别比肠道细胞系高2.5倍和6.6倍。黄酮类化合物未能影响LLC-PK1和MCF-7细胞的凋亡，而黄芩素和杨梅素能够诱导HT-29和Caco-2细胞凋亡。总之，黄酮、黄酮醇类、黄烷酮类和异黄酮类黄酮化合物在不同癌细胞系中具有抗增殖作用。黄酮类化合物的生长抑制和诱导凋亡能力无法根据其化学成分和结构来预测。
