Development of a Potent Inhibitor of Metastasis Based on a Cyclic Lysophosphatidic Acid

基于环状溶血磷脂酸的有效转移抑制剂的开发

• 批准号: 13557212
• 负责人: KOBAYASHI Susumu
• 金额: $ 8.58万
• 依托单位: Tokyo University of Science
• 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 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13557212/
• 关键词: Metastasis; Tumor cell invasion; phospholipid; Cyclic phosphatidic acid; Phosphatidic acid; Lysophosphatidic acid; 癌細胞の浸潤; アポトーシス誘導作用

Cyclic phosphatidic acid (1-acyl-sn-glycero-2,3-cyclic phosphate; cPA) is a naturally occurring analog of lysophosphatidic acid (LPA) with a variety of distinctly different biological activities from those of LPA. In sharp contrast to LPA, a potent inducer of tumor cell invasion, we previously discovered that palmitoyl-cPA inhibits FBS- and LPA-induced transcellular migration and metastasis. Cyclic phosphate is not a stable molecule. It might be hydrolyzed either by chemically or enzymatically. In this regard, we have observed that LPA and cPA are enzymatically produced from phosphatidyl choline by phospholipase D (PLD). It is quite important to design a novel molecule of cPA origin which resists to hydrolysis because resulting hydrolyzed product, LPA is known to induce metastasis. In order to prevent the conversion of cPL to LPA, we carried out a modification on cyclic phosphate moiety. One of the molecules which we designed is a carba analog. Carba derivatives, in which the phosphate oxygen was replaced with a methylene group either at the sn-2 or the sn-3 position, showed much more potent inhibitory effects on MM! tumor cell transcellular migration and the pulmonary metastasis of B16-F0 melanoma than the natural Pal-cPA. The antimetastatic effect of carba-cPA was accompanied by the inhibition of Pho activation and was not due to the inhibition or the activation of LPA receptors.

环磷脂酸(CPA)是溶血磷脂酸(LPA)的天然类似物，具有许多与LPA截然不同的生物活性。与强大的肿瘤细胞侵袭诱导剂LPA形成鲜明对比的是，我们先前发现Palmitoyl-CPA抑制了FBS和LPA诱导的跨细胞迁移和转移。环磷酸盐不是一个稳定的分子。它可以通过化学或酶的方式进行水解。在这方面，我们观察到LPA和CPA是由磷脂酶D(PLD)催化磷脂酰胆碱产生的。设计一种抗水解性的CPA来源的新型分子是非常重要的，因为水解物LPA可诱导肿瘤转移。为了防止CPL转化为LPA，我们对环磷酸部分进行了修饰。我们设计的其中一个分子是碳水化合物类似物。其中，在sn-2或sn-3位用亚甲基取代磷酸氧的CABA衍生物对MM显示出更强的抑制作用！与天然Pal-CPA相比，B16-F0黑色素瘤的肿瘤细胞跨细胞迁移和肺转移。Carba-CPA的抗转移作用伴随着Pho激活的抑制，而不是LPA受体的抑制或激活。

项目成果

Attenuation by Cyclic Phosphatidic Acid of Peritoncal Metastasis of Azoxymethanc-Induced Intestinal Cancers in Wister Rats

环磷脂酸对 Wister 大鼠中氧化偶氮甲烷诱导的肠癌腹膜转移的减弱作用

• 发表时间: 2004
• 期刊: Int. J. Cancer 110・2
• 作者: 石原 龍

向井 睦子: "Cyclic phosphatidic acid inhibits RhoA-mediated autophosphorylation of FAK at Tyr-397 and subsequent tumor-cell invasion"Int.J.Oncology. 22巻. 1247-1256 (2003)

Mutsuko Mukai：“环状磷脂酸抑制 Tyr-397 处 RhoA 介导的 FAK 自身磷酸化和随后的肿瘤细胞侵袭”Int.J.Oncology 22. 1247-1256 (2003)

國本正子: "Steryl Glucoside is a Lipid Mediator in Stress-responsive Signal Transduction"Cell Struct. Funct.. 27巻. 157-162 (2002)

Masako Kunimoto：“甾基葡萄糖苷是应激反应信号转导中的脂质介质”细胞结构。卷 27. 157-162 (2002)

内呂 拓実: "Total Synthesis and Antifungal Activity of 9-Methoxystrobirulin L as the Originally Proposed 1,4-Benzodioxan Structure"Bioorg.Med.Chem.Lett.. 11巻. 2783-2786 (2001)

Takumi Uchiro：“9-甲氧基球菌素 L 作为最初提出的 1,4-苯并二恶烷结构的全合成和抗真菌活性”Bioorg.Med.Chem.Lett.. Vol. 11. 2783-2786 (2001)

Steryl glucoside is a lipid mediator in stress-responsive signal transduction

• DOI: 10.1247/csf.27.157
• 发表时间: 2002-06-01
• 期刊: CELL STRUCTURE AND FUNCTION
• 影响因子: 1.5
• 作者: Kunimoto, S;Murofushi, W;Murakami-Murofushi, K
• 通讯作者: Murakami-Murofushi, K