Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid

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...

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Published in:	Biochimica et biophysica acta Vol. 1771; no. 1; pp. 103 - 112
Main Authors:	Uchiyama, Ayako, Mukai, Mutsuko, Fujiwara, Yuko, Kobayashi, Susumu, Kawai, Nobuyuki, Murofushi, Hiromu, Inoue, Masahiro, Enoki, Shigenori, Tanaka, Yuichiro, Niki, Tamotsu, Kobayashi, Tetsuyuki, Tigyi, Gabor, Murakami-Murofushi, Kimiko
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-01-2007
Subjects:	Animals Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Cell Movement - drug effects Cyclic phosphatidic acid Enzyme Activation - drug effects Humans Invasion Lung Neoplasms - metabolism Lung Neoplasms - mortality Lung Neoplasms - prevention & control Lung Neoplasms - secondary Lysophosphatidic acid, LPA Lysophospholipids - chemical synthesis Lysophospholipids - chemistry Lysophospholipids - pharmacology Melanoma - drug therapy Melanoma - metabolism Melanoma - pathology Metastasis Mice Neoplasm Metastasis Phosphatidic Acids - chemical synthesis Phosphatidic Acids - chemistry Phosphatidic Acids - pharmacology Rats rhoA GTP-Binding Protein - antagonists & inhibitors Xenograft Model Antitumor Assays Lysophosphatidic acid, LPA Metastasis Cyclic phosphatidic acid Invasion
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Summary:	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-F0 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.
ISSN:	1388-1981 0006-3002 1879-2618
DOI:	10.1016/j.bbalip.2006.10.001