Benzochromenones from the marine crinoid Comantheria rotula inhibit hypoxia-inducible factor-1 (HIF-1) in cell-based reporter assays and differentially suppress the growth of certain tumor cell lines
Benzochromenones from the marine crinoid Comantheria rotula inhibit hypoxia-inducible factor-1 (HIF-1) in cell-based reporter assays and differentially suppress the growth of certain tumor cell lines
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DOI：
10.1021/np070224w
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发表时间：
2007-09-01
影响因子：
5.1
通讯作者：
Nagle, Dale G.
中科院分区：
文献类型：
--
作者：
Dai, Jingqiu;Liu, Yang;Nagle, Dale G.
缺氧诱导因子-1 （hypoxia inducible factor-1, HIF-1）是一种促进肿瘤细胞在缺氧条件下适应和存活的转录因子。HIF-1是目前公认的抗癌药物发现的重要分子靶点。国家癌症研究所开放的海洋无脊椎动物和藻类脂质提取物储存库使用基于T47D乳腺肿瘤细胞的报告细胞试验来评估HIF-1抑制活性。在生物测定指导下，从一种红百合（Comantheria rotula）中提取了一种活性提取物，得到了七种苯并[g] -4- 1和苯并[h] -4- 1色素（1-7）。从光谱和光谱分析数据推断了新的苯并[g]铬酮二聚体9,9'-氧-新紫花色素(1)和另一种新的天然色素5的结构。在乳腺和前列腺肿瘤细胞中，红百合色素显著抑制缺氧诱导和地铁螯合剂诱导的HIF-1荧光素酶报告活性。然而，在报告实验中，HIF-1的抑制并没有转化为下游HIF-1靶点——分泌的血管内皮生长因子（VEGF）表达的显著降低。在NCI 60细胞系面板中发现化合物1具有抑制肿瘤细胞生长的作用（GI（50）值为1.6 ~ 18.2 μ M），化合物6具有独特的抑制肿瘤细胞生长的模式。5个不同器官的细胞系对6 （GI（50）值为0.29 ~ 0.62 μ M）敏感，3个中等敏感（GI（50）值为2.2 ~ 5.1 μ M），其余大多数细胞系的GI（50）值在20 ~ 47 μ M之间。改良的DPPH实验还发现，类海参苯并[g]染色体具有清除自由基的作用。
Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that promotes tumor cell adaptation and survival under hypoxic conditions. HIF-1 is currently recognized as an important molecular target for anticancer drug discovery. The National Cancer Institute open repository of marine invertebrates and algae lipid extracts was evaluated using a T47D breast tumor cell-based reporter assay for HIF-1 inhibitory activity. Bioassay-guided fractionation of an active extract from a crinoid Comantheria rotula yielded seven benzo[g]chromen-4-one and benzo[h]chromen-4-one pigments (1-7). The structures of the new benzo[g]chromenone dimer 9,9'-oxybis-neocomantherin (1) and another new natural pigment 5 were deduced from spectroscopic and spectrometric data. The crinoid pigments significantly inhibited both hypoxia-induced andiron chelator-induced HIF-1 luciferase reporter activity in breast and prostate tumor cells. However, inhibition of HIF-1 in the reporter assay did not translate into a significant decrease in the expression of the downstream HIF-1 target, secreted vascular endothelial growth factor (VEGF). Compound I was found to inhibit tumor cell growth in the NCI 60-cell line panel (GI(50) values of 1.6-18.2 mu M), and compound 6 produced a unique pattern of tumor cell growth suppression. Five cell lines from different organs were hypersensitive to 6 (GI(50) values of 0.29-0.62 mu M), and three others were moderately sensitive (GI(50) values of 2.2-5.1 mu M), while the GI(50) values for most other cell lines ranged from 20 to 47 mu M. Crinoid benzo[g]chromenones were also found to scavenge radicals in a modified DPPH assay.