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CELL DEATH AND POLYAMINE

细胞死亡和多胺

基本信息

批准号：
06807173
负责人：
SHIRAHATA Akira
金额：
$ 1.15万
依托单位：
JOSAI UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06807173/
关键词：
Polyamine Spermidine Cell death Polyamine oxidase Polyamine transport Diacetylpolyamine アポトーシス

项目摘要

It was found that administration of spermidine to cultured rat hepatoma (HTC) cells depleted of polyamine with ornithine decarboxylase inhibitor, 1-aminooxy-3-aminopropane (AOAP), 1ed to an abnormal accumulation of cellular spermidine followed by the cell death. although, some morphorogical features suggested it was apoptosis, mitocondrial damage was observed in electron micrograph and a clear fragmentation of DNA was not observed in the analysis of cellular DNA by gel electrophoresis.Mechanism of tha abnormal accumulation of spermidine was examined. It was found that the accumulation was dependent on the exposure period of AOAP to the cells, and that the longer exposure of AOAP inhibited repression of spermidine uptake activity. As protein synthesis rate was decreased to 20% of control by the longer exposue of AOAP,it was suggested that inhibition of synthesis of a protein by the long exposure of AOAP to the cells which was needed in the repression of spermidine uptake activity led to the abnormal accumulation of spermidine.In order to develope a prodrug which enable us to introduce excess polyamine into cells diacetly derivatives of polyamine were synthesized and examined. It was found that diacetyl pentaamines were good substrates of polyamine uptake system and polyamine oxidase, and then efficiently converted into spermidine or norspermidine in HTC cells. But these compounds were not successfully taken into the cells to an abnormal accumulation level, suggesting that the srtucture which does not utilize polyamine transport system is needed for the compound to be accumulate to excess level in cells.

研究发现，用鸟氨酸脱羧酶抑制剂1-氨基氧基-3-氨基丙烷（AOAP）对培养的多胺缺失的大鼠肝癌（HTC）细胞给予亚精胺可导致细胞亚精胺的异常积累，随后导致细胞死亡。电镜观察到线粒体损伤，凝胶电泳细胞DNA分析未见明显的DNA断裂。探讨了亚精胺异常积累的机制。结果表明，亚精胺的积累与AOAP暴露于细胞的时间有关，AOAP暴露时间越长，其对亚精胺摄取活性的抑制作用越明显。由于长时间暴露于AOAP使蛋白质合成率降低到对照的20%，因此，这表明AOAP长期暴露于细胞抑制亚精胺摄取活性所需的蛋白质合成，导致了亚精胺的异常积累。为了开发一种能将过量多胺引入细胞的前药，我们合成并研究了多胺的直接衍生物。发现二乙酰五胺是多胺摄取系统和多胺氧化酶的良好底物，在HTC细胞内有效转化为亚精胺或去亚精胺。但这些化合物在细胞内并没有成功积累到异常水平，这表明这些化合物在细胞内积累到过量水平需要不利用多胺转运系统的结构。