Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid
Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid
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DOI：
10.1016/j.bbalip.2006.10.001
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发表时间：
2007-01-01
影响因子：
4.8
通讯作者：
Murakami-Murofushi, Kimiko
中科院分区：
文献类型：
--
作者：
Uchiyama, Ayako;Mukai, Mutsuko;Murakami-Murofushi, Kimiko
环磷脂酸（1-酰基-sn-甘油-2，3-环磷酸; cPA）是溶血磷脂酸（LPA）的天然存在的类似物，具有与LPA的那些明显不同的多种生物活性。与肿瘤细胞侵袭的有效诱导剂LPA相反，棕榈酰-cPA抑制FBS和LPA诱导的跨细胞迁移和转移。为了防止cPA转化为LPA，我们通过稳定环状磷酸酯环合成了cPA衍生物;为了防止脂肪酸裂解，我们生成了cPA的烷基醚类似物。测试两组化合物对跨细胞肿瘤细胞迁移的抑制活性。Carba衍生物，其中磷酸氧在sn-2或sn-3位置被亚甲基取代，对MM 1肿瘤细胞跨细胞迁移和B16-FO黑色素瘤肺转移的抑制作用比天然pal-cPA强得多。carba-cPA的抗转移作用伴随着RhoA活化的抑制，而不是由于LPA受体活化的抑制。(c)2006 Elsevier B. V.保留所有权利。
Cyclic phosphatidic acid (1-acyl-sn-glycerol-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 contrast to LPA, a potent inducer of tumor cell invasion, palmitoyl-cPA inhibits FBS- and LPA-induced transcellular migration and metastasis. To prevent the conversion of cPA to LPA we synthesized cPA derivatives by stabilizing the cyclic phosphate ring; to prevent the cleavage of the fatty acid we generated alkyl ether analogs of cPA. Both sets of compounds were tested for inhibitory activity on transcellular tumor cell migration. Carba derivatives, in which the phosphate oxygen was replaced with a methylene group at either the sn-2 or the sn-3 position, showed much more potent inhibitory effects on MM1 tumor cell transcellular migration and the pulmonary metastasis of B16-FO melanoma than the natural pal-cPA. The antimetastatic effect of carba-cPA was accompanied by the inhibition of RhoA activation and was not due to inhibition of the activation of LPA receptors. (c) 2006 Elsevier B.V. All rights reserved.