Flavaglines: A group of efficient growth inhibitors block cell cycle progression and induce apoptosis in colorectal cancer cells
Flavaglines: A group of efficient growth inhibitors block cell cycle progression and induce apoptosis in colorectal cancer cells
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DOI：
10.1002/ijc.20033
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发表时间：
2004-05-10
影响因子：
6.4
通讯作者：
Marian, B
中科院分区：
文献类型：
--
作者：
Hausott, B;Greger, H;Marian, B
黄萎线是黄酮醇-肉桂酸酯衍生的环戊烷-a[b]苯并呋喃类化合物，到目前为止只报道了十字花科植物中的仙人掌属。它们代表了一组高度生物活性的代谢物，已经以其强大的抗白血病活性而闻名。为了评估它们作为结直肠癌化疗药物的适宜性，分析了它们在结直肠癌细胞系中的细胞抑制作用和潜在的作用机制。在SW480和HT29/HI1癌细胞中，Aglaiastatin的活性最强，在纳摩尔浓度下抑制生长和诱导细胞凋亡，而癌前肿瘤细胞株VACO235和LT97以及正常肠上皮细胞株IEC18的敏感性较低(IC50和10um)。在SW480细胞中，加药后24小时和48小时细胞周期分布发生改变，6小时后细胞周期蛋白B含量增加，2小时细胞周期蛋白A水平降低。此外，凋亡细胞核的特征性形态、基质金属蛋白酶的丢失和bcl(Xl)的下调也可作为诱导细胞凋亡的指标。暴露2小时后观察到p38的强烈激活，表明细胞凋亡可能是通过p38介导的应激途径诱导的。(C)2004年Wiley-Liss公司
Flavaglines are flavonol-cinnamate-derived cyclopent-a[b]benzofurans, so far reported only for the genus Aglaia of the plant family Meliaceae. They represent a group of highly bioactive metabolites already known for their strong anti-leukemic activities. To assess their suitability as chemotherapeutic drugs in colorectal cancer, their cytostatic effects and the underlying mechanisms of action were analyzed in colorectal tumor cell lines. Aglaiastatin was the most active flavagline, inhibiting growth and inducing apoptosis at nanomolar concentrations in SW480 and HT29/HI1 carcinoma cells, while the premalignant adenoma cell lines VACO235 and LT97 as well as the normal intestinal epithelial cell line IEC18 were 1,000 times less sensitive (IC50 > 10 muM). In SW480 cells, aglaiastatin caused cell cycle block in early mitosis, demonstrated by a shift of cell cycle distribution 24 and 48 hr after addition of aglaiastatin and by an increased content of cyclin B after 6 hr together with a decreased level of cyclin A as early as 2 hr after exposure. In addition, induction of apoptosis could be shown by the characteristic morphology of apoptotic nuclei, loss of MMP and downmodulation of bcl(xl). Strong activation of p38 was observed after 2 hr of exposure, indicating that apoptosis may be induced via a p38-mediated stress pathway. (C) 2004 Wiley-Liss, Inc.