Death receptor 5 targeting activity-guided isolation of isoflavones from Millettia brandisiana and Ardisia colorata and evaluation of ability to induce TRAIL-mediated apoptosis
Death receptor 5 targeting activity-guided isolation of isoflavones from Millettia brandisiana and Ardisia colorata and evaluation of ability to induce TRAIL-mediated apoptosis
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DOI：
10.1016/j.bmc.2008.12.033
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发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Ishibashi, Masami
中科院分区：
文献类型：
--
作者：
Kikuchi, Hiroyuki;Ohtsuki, Takashi;Ishibashi, Masami
死亡受体5(DR5)是肿瘤坏死因子相关的凋亡诱导配体(TRAIL)的凋亡诱导膜受体。在利用DLD-1/SacI荧光素酶活性法筛选促进DR5表达的化合物时，我们先前鉴定了从千金莲叶片中分离到的4‘-去甲基毒性异黄酮类(1)。在这项研究中，我们揭示了1通过上调DR5的表达来增敏TRAIL耐药的人胃腺癌(AGS)细胞对TRAIL诱导的细胞凋亡。1诱导DR5在mRNA和蛋白水平表达。人重组DR5/Fc嵌合体可显著抑制1-甲氧基异丙基异构体诱导的细胞凋亡。这些结果表明，1对DR5表达的增强是细胞死亡的关键。此外，在这个筛选体系中，紫金莲皮的甲醇提取物显著增强了DR5的活性。生物测定引导的分离导致分离和鉴定了一个新的异黄酮，花色单宁A(3)，以及10个已知的化合物。通过波谱分析，确定了新化合物的化学结构。(C)2008爱思唯尔有限公司。保留所有权利。
Death receptor 5 (DR5) is an apoptosis-inducing membrane receptor for TNF-related apoptosis-inducing ligand ( TRAIL). On screening for compounds that enhance DR5 expression using a luciferase assay with DLD-1/SacI, we previously identified 4'-demethyltoxicarol isoflavone ( 1) isolated from the leaves of Millettia brandisiana. In this study, we revealed that 1 sensitized TRAIL-resistant human gastric adenocarcinoma (AGS) cells to TRAIL-induced apoptosis by up-regulating the expression of DR5. 1 induced DR5 expression at both the mRNA and protein level. A human recombinant DR5/Fc chimera remarkably inhibited 1-induced apoptosis. These results suggest that the enhancement of DR5 expression by 1 was critical to the cell death. Furthermore, a MeOH extract of the bark of Ardisia colorata markedly enhanced DR5 activity in this screening system. Bioassay-guided fractionation of A. colorata led to the isolation and identification of a new isoflavone, coloratanin A ( 3), together with ten known compounds. The chemical structure of the new compound was elucidated on the basis of a spectroscopic analysis. (c) 2008 Elsevier Ltd. All rights reserved.