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SEARCH FOR ANTI-METASTATIC AND DIFFERENTIATION-INDUCING ACTIVE COMPOUNDS FROM MEDICINAL PLANTS AND FOODS

从药用植物和食品中寻找抗转移和诱导分化的活性化合物

基本信息

批准号：
16510168
负责人：
MATSUDA Hisashi
金额：
$ 2.24万
依托单位：
KYOTO PHARMACEUTICAL UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

In the present study, we investigated the active constituents with anti-invasive, matrix metalloproteases (MMPs) production inhibitory, differentiation-inducing activities from medicinal plants that have been used for anti-cancer and longevity.1.The MeOH extract and EtOAc-soluble fraction traditional Thai medicine, the stems of Erycibe expansa (Convolvulaceae) were found to inhibit invasion of HT1080 cells through Matrigel-coated filters in vitro and proliferation of human fibroblast (HT1080) and human leukemia cell (U937) cells. Through bioassay-guided separation, four principal rotenoids [deguelin (1), tephrosin (2), rotenone (3), 12a-hydroxyrotenone (4)] together with various isoflavones and pterocarpanes were isolated from the EtOAc fraction. Among them, 1-4 inhibited the invasion of HT1080 cells at 3-30 μM after 24 h incubation, and they also inhibited proliferation of HT1080 and human leukemia U937 cells after 48 h incubation. With regard to their action mechanism, 1-4 (1-10 μM) … More inhibited release of proMMP-9 in the medium using a gelatin zymography. Furthermore, compounds 1 and 2 (10 μM) induced the differentiation of HL-60 cells using NBT reduction test.2.The methanolic extract and its alkaloid fraction from the rhizomes of Nuphar pumilum were found show cytotoxic effects on U937, mouse melanoma cell (B16F10), and HT1080 in the experiments of their anti-invasion. Dimeric sesquiterpene thioalkaloids with the 6-hydroxyl group (6-hydroxythiobinupharidine, 6,6'-dihydroxythiobinupharidine, 6-hydroxythionuphlutine B) showed substantial cytotoxic activity at a concentration of 10 μM, and several structural requiremwnts for the activity were clarified. Apoptosis of U937 was immediately observed within 1 h after treatment of 6-hydroxythiobinupharidine and pathway via caspase-8 was found to be involved.3.Furthermore, new diterpene alkaloids, nigellamines were isolated from the seeds of Nigella sativa that have been used for cancer treatment and their chemical structures were determined. 1'S-1'-Acetoxychavicol acetate and various related compounds were found to inhibit activation of NF-κB, suggesting antitumor activity. Less

在本研究中，我们研究了已用于抗癌和长寿的药用植物中具有抗侵袭、抑制基质金属蛋白酶(MMPs)产生、诱导分化活性的活性成分。1.泰国传统药物Erycibe expansa(旋花科)茎的甲醇提取物和EtOAc可溶部分在体外通过Matrigel涂层滤膜抑制HT1080细胞的侵袭和人成纤维细胞(HT1080)和人白血病细胞(U937)的增殖。通过生物测定引导分离，从乙酸乙酯提取物中分离得到4个主要鱼烯类化合物[鱼藤素(1)、陈皮松(2)、鱼藤酮(3)、12A-羟鱼藤酮(4)]以及各种异黄酮类和萜类化合物。其中，1-4在孵育24 h后3-30μM对HT1080细胞的侵袭有抑制作用，48 h对HT1080和人白血病U937细胞的增殖也有抑制作用。关于它们的作用机制，1-4(1-10μM)…明胶酶谱显示，基质中的原基质金属蛋白酶-9的释放受到更多的抑制。此外，化合物1和2(10μM)对HL-60细胞有明显的诱导分化作用。2.在抗侵袭实验中，研究发现，小豆根乙醇提取物及其生物碱部位对U937、小鼠黑色素瘤细胞(B16F10)和HT1080细胞均具有细胞毒作用。含6-羟基的倍半萜类二聚体生物碱(6-羟基硫代丁香苷、6，6‘-二羟基硫代丁香碱、6-羟基硫代胡萝卜素B)在10μM的浓度下表现出较强的细胞毒活性，并阐明了该活性的几个结构要求。6-羟基硫代丁烷处理U937后1h内即可观察到U937细胞发生凋亡，并通过caspase-8途径参与其中。3.从已用于治疗癌症的黑种草种子中分离得到新的二萜生物碱和黑麦拉胺类化合物，并对其化学结构进行了鉴定。1‘S-1’-乙酰氧基查维酮醋酸酯及其相关化合物可抑制核因子-κB的活化，提示其具有抗肿瘤活性。较少