Development of cancer preventing agent using conjugated trienoic fatty acids

使用共轭三烯脂肪酸开发癌症预防剂

• 批准号: 13556016
• 负责人: MIYAZAWA Teruo
• 金额: $ 4.35万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13556016/
• 关键词: Conjugated fatty acid; Conjugated triene; Colon cancer; Apoptosis; Lipid peroxidation; Anticarcinogenesis; Lipid metabolism; ヌードマウス; 酸化ストレス; 大量調製法

We found out that conjugated eicosapentaenoic acid (CEPA) and conjugated docosahexaenoic acid (CDHA) with conjugated trienoic structure, have the strongest cytotoxic effect selectively on human tumor cell lines. The incorporation of these conjugated fatty acids is sufficient to increase the sensitivity to oxidative damage that is indicative for apoptotic cell death. The CEPA with triene structure, prepared by aikaline treatment, showed intensive toxicity with DLD-1 cell (colorectal adenocarcinoma) -transplanted tumor in male athymic nude mice. The anticarcinogenic activity involved membrane phospholipid peroxidation. CEPA induced DNA fragmentation in DLD-1 cell-transplanted tumor in nude mice, indicating the involvement of apoptosis in the anticarcinogenic mechanism.The occurrence of a significant amount of 9, 11-conjugated linoleic acid (CLA, 9, 11-18:2) was confirmed in the liver and plasma lipids of rats fed a 1% (w/w % of diet) eleostearic acid (ESA, 9, 11, 13-18:3) diet. The chemical structure of 9, 11-CLA was identified by gas chromatography-electron impact mass spectrometry after its conversion to a 4, 4-dimethyloxazoline derivative. The concentration of CLA in the total fatty acids of the liver and plasma lipids reached to 1% for each in the CLA-supplemented rats, while reaching 3.2% and 2.5%, respectively, in the ESA-supplemented rats. The α-ESA was shown to be metabolized partially to CLA via a delta 13-saturation reaction in the rat. Some biological activities observed in α-ESA-fed animals may be ascribed also to CLA that is formed from ESA in the body.

我们发现具有共轭三烯结构的共轭二十碳五烯酸（CEPA）和共轭二十二碳六烯酸（CDHA）对人肿瘤细胞株具有最强的选择性细胞毒作用。这些共轭脂肪酸的掺入足以增加对指示凋亡性细胞死亡的氧化损伤的敏感性。碱处理法制备的三烯结构CEPA对DLD-1结肠癌裸鼠移植瘤有明显的毒性作用。抗癌活性涉及膜磷脂过氧化。CEPA可诱导DLD-1细胞裸鼠移植瘤的DNA断裂，提示细胞凋亡参与了其抗癌机制，并证实了1%（w/w %）桐酸（ESA，9，11，13-18：3）饲料喂养的大鼠肝脏和血浆脂质中出现了大量的9，11-共轭亚油酸（CLA，9，11 - 18：2）。9，11-CLA转化为4，4-二甲基恶唑啉衍生物后，通过气相色谱-电子轰击质谱法鉴定了其化学结构。CLA在肝脏总脂肪酸和血浆脂质中的浓度在补充CLA的大鼠中分别达到1%，而在补充ESA的大鼠中分别达到3.2%和2.5%。在大鼠体内，α-ESA通过δ 13-饱和反应部分代谢为CLA。在饲喂α-ESA的动物中观察到的一些生物活性也可能归因于体内ESA形成的CLA。

项目成果

Tsuyashi Tsuzuki: "A metabolic conversion from 9,11,13-eleostearic acid(18:3,n-5)to 9,11-conjugated linoleis acid(18:12,n-7) in the rat"Journal of Nutritional Science and Vitaminology. 49・1(発売予定). (2003)

Tsuyashi Tsuzuki：“大鼠体内从 9,11,13-桐油酸 (18:3,n-5) 到 9,11-共轭亚油酸 (18:12,n-7) 的代谢转化”营养科学杂志和维生素学。49・1（预定发布）（2003 年）。

Tatsuya Sugawara: "Apoptosis induction by wheat-flour sphingeid bases in DLD-1 human cancer cells"Bioscience, Biotechn-logy, and Biochemistry. 66・10. 2228-2231 (2002)

菅原达也：“小麦粉鞘氨醇碱在 DLD-1 人类癌细胞中诱导细胞凋亡”《生物科学、生物技术和生物化学》66・10（2002 年）。

Tsuyoshi Tsuzuki: "The Metabolic Conversion of 9,11,13-eleostearic acid (18:3) to 9,11-conjugated Linoleic Acid (18:2) in the Rat"Journal of Nutritional Science and Vitaminology. 49・3(発表予定). (2003)

Tsuyoshi Tsuzuki：“大鼠体内 9,11,13-桐油酸 (18:3) 向 9,11-共轭亚油酸 (18:2) 的代谢转化”营养科学与维生素学杂志 49・3（演示文稿） ）（计划）（2003）。

K.Moriya: "Oxidative stress in the absence of inflamation in a mouse model for hepatitis C virus-associated hepatocarcinogenesis"Cancer Research. 61. 4365-4370 (2001)

K.Moriya：“丙型肝炎病毒相关肝癌发生的小鼠模型中无炎症情况下的氧化应激”癌症研究。

Miki Igarashi: "The growth inhibitory effect of conjugated linoleic acid on a human hepatoma cell line, HepG2, is induced by a change in fatty acid metabolism, but not the facilitation of lipid peroxidation in the cells"Biochimica et Biophysica Acta. 1530

Miki Igarashi：“共轭亚油酸对人肝癌细胞系 HepG2 的生长抑制作用是由脂肪酸代谢的变化引起的，而不是细胞中脂质过氧化的促进”Biochimica et Biophysica Acta。