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 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.
Uchiyama
Ayako
A
Department of Biology, Faculty of Science, Ochanomizu University, 2-1-1 Ohtsuka, Tokyo 112-8610, Japan.
Mukai
Mutsuko
M
Fujiwara
Yuko
Y
Kobayashi
Susumu
S
Kawai
Nobuyuki
N
Murofushi
Hiromu
H
Inoue
Masahiro
M
Enoki
Shigenori
S
Tanaka
Yuichiro
Y
Niki
Tamotsu
T
Kobayashi
Tetsuyuki
T
Tigyi
Gabor
G
Murakami-Murofushi
Kimiko
K
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
D000970:Antineoplastic Agents; D008246:Lysophospholipids; D010712:Phosphatidic Acids; D020742:rhoA GTP-Binding Protein