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Investigation of natural products with selective cytotoxicity against tumor cells

对肿瘤细胞具有选择性细胞毒性的天然产物的研究

基本信息

批准号：
10470472
负责人：
OGIHARA Yukio
金额：
$ 2.82万
依托单位：
Nagoya City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470472/
关键词：
Gallic Acid Zephyranthes alkaloids Apoptosis Selectivity FK506 binding protein 12 Peptidyl-prolyl cis-trans isomerase Histone H3 FK506 binding protein12 没食子酸誘導体細胞死カルシウム活性酸素

项目摘要

In this study, the mechanism by which natural products, gallic acid and Zephyranthes alkaloids, show selective cytotoxicity against tumor cells relative to normal cells was investigated. In apoptosis induced by gallic acid, some proteins increased after gallic acid treatment. Among them, N-terminal amino acid sequences of three proteins were determined and were found to have high homology with FK506 binding protein 12 (FKBP12), peptidyl-prolyl cis-trans isomerase (Pin-1), and histone H3. Furthermore, mRNA levels of FKBP12 and Pin-1 was elevated, thus indicating that these two proteins should be synthesized after gallic acid treatment. Further study indicated that gallic acid first generated reactive oxygen species and then increased intracellular CaィイD1++ィエD1, followed by increase of FKBP12, Pin-1 and histone H3. The pricise mechanism of these three proteins in gallic acid-induced apoptosis remained to be determined.1-(3-Hydroxybutylyl)pancratistatin (HBP) and 1-((S)-(+)-3-beta-D-glucopyranosyloxybutylyl) pancratistatin (GBP) were isolated from Zephyranthes carinata and was found to induce apoptosis in tumor cells. GBP inhibited cell growth at G0/G1 and G2/M phases. On the other hand, HBP prevented cell growth at G0/G1, S, and G2/M phases. That is, both compounds influenced the machinery of cell cycle to result in inhibition of cell growth and apoptosis induction.

本研究探讨了天然产物没食子酸和泽兰生物碱相对于正常细胞对肿瘤细胞的选择性杀伤作用的机制。在没食子酸诱导的细胞凋亡中，有一些蛋白质在没食子酸处理后增加。其中3个蛋白质的N端氨基酸序列与FK506结合蛋白12(FKBP12)、肽基-脯氨基顺反异构酶(Pin-1)和组蛋白H3有很高的同源性。此外，FKBP12和Pin-1的mRNA水平升高，表明这两种蛋白在没食子酸处理后应该合成。进一步的研究表明，没食子酸首先产生活性氧，然后使细胞内CaィイD1++ィエD1增加，然后是FKBP12、Pin-1和组蛋白H3的增加。这三种蛋白在没食子酸诱导细胞凋亡中的作用机制尚不清楚。1-(3-羟基丁基)泛抑素(HBP)和1-((S)-(+)-3-β-D-吡喃葡萄糖氧基丁基)泛抑素(GBP)是从龙须草中分离得到的，具有诱导肿瘤细胞凋亡的作用。GBP抑制细胞生长于G0/G1期和G2/M期。另一方面，HBP抑制细胞生长于G0/G1期、S期和G2/M期。也就是说，这两种化合物都影响了细胞周期机制，导致抑制细胞生长和诱导细胞凋亡。