title: Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid.
abstract: 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.
authors.affiliation: Department of Biology, Faculty of Science, Ochanomizu University, 2-1-1 Ohtsuka, Tokyo 112-8610, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Uchiyama
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Mukai
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Susumu
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kawai
authors.forename: Hiromu
authors.initials: H
authors.lastname: Murofushi
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.forename: Shigenori
authors.initials: S
authors.lastname: Enoki
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Niki
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.forename: Kimiko
authors.initials: K
authors.lastname: Murakami-Murofushi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control* / Q000556:secondary; D008246:Lysophospholipids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D010712:Phosphatidic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D023041:Xenograft Model Antitumor Assays; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D008246:Lysophospholipids; D010712:Phosphatidic Acids; D020742:rhoA GTP-Binding Protein