Berberine acts as a natural inhibitor of Wnt/β-catenin signaling-Identification of more active 13-arylalkyl derivatives
Berberine acts as a natural inhibitor of Wnt/β-catenin signaling-Identification of more active 13-arylalkyl derivatives
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DOI：
10.1002/biof.1133
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发表时间：
2013-11-01
期刊：
影响因子：
6
通讯作者：
Huber, Otmar
中科院分区：
文献类型：
--
作者：
Albring, Kai Frederik;Weidemueller, Julia;Huber, Otmar
据报道，许多不同来源的肿瘤都存在经典 Wnt/-catenin 信号通路的异常激活。在大多数情况下，检测到 Wnt 信号通路成分或β-连环蛋白本身的突变，最终诱导促进细胞增殖和减弱细胞凋亡的遗传程序。因此，Wnt/-连环蛋白信号传导的靶向具有特定的治疗意义。在此，我们研究了植物来源的异喹啉生物碱小檗碱（据报道具有抗癌活性）及其合成的 13-芳基烷基衍生物对 Wnt/-连环蛋白信号传导的影响。小檗碱对 HEK-293 胚胎肾和 HCT116 结肠癌细胞的活力没有表现出重大影响，并且在浓度高达 20 μM 时也没有毒性。小檗碱抑制 β 连环蛋白转录活性并减弱不依赖贴壁的生长。小檗碱治疗的结果是，活性β-连环蛋白的细胞水平降低，同时E-钙粘蛋白表达增加。然而，在未刺激的细胞中，对β-连环蛋白水平的影响很低。对合成 13-芳烷基小檗碱衍生物的筛选鉴定出化合物的活性优于天然存在的母体物质，其 Wnt 抑制的 EC50 值低 100 倍以上。因此，小檗碱及其合成衍生物代表了抑制肿瘤发生中Wnt/-连环蛋白信号传导的潜在治疗剂。 (c) 2013 年生物因子，39(6):652-662，2013 年
Aberrant activation of the canonical Wnt/-catenin signaling pathway has been reported for numerous tumors of different origins. In most cases, mutations in components of the Wnt signaling pathway or in -catenin itself were detected which ultimately induce a genetic program that promotes cell proliferation and attenuates apoptosis. Thus, targeting of Wnt/-catenin signaling is of specific therapeutic interest. Herein, we investigated the plant-derived isoquinoline alkaloid berberine, which has been reported to have anticancer activity, and synthetic 13-arylalkyl derivatives thereof for their effects on Wnt/-catenin signaling. Berberine did not show major effects on viability of HEK-293 embryonic kidney and HCT116 colon carcinoma cells and was not toxic in concentrations up to 20 mu M. Berberine inhibited -catenin transcriptional activity and attenuated anchorage-independent growth. As a result of berberine treatment, cellular levels of active -catenin were reduced concomitant with an increase in the expression of E-cadherin. However, in unstimulated cells, the effects on -catenin levels were low. A screen of synthetic 13-arylalkyl berberine derivatives identified compounds exhibiting activities superior to those of the naturally occurring parent substance with more than 100-fold lower EC50 values for Wnt-repression. Thus, berberine and its synthetic derivatives represent potential therapeutic agents to inhibit Wnt/-catenin signaling in tumorigenesis. (c) 2013 BioFactors, 39(6):652-662, 2013