Description
Cyclic phosphatidic acids (cPAs) are naturally occurring analogs of lysophosphatidic acid (LPA) in which the
sn-
2 hydroxy group forms a 5-
membered ring with the
sn-
3 phosphate.
1,2 Carba-
derivatives of cPA (ccPA) are modified at the
sn-
2 (2-
ccPA) or
sn-
3 (3-
ccPA) linkage, preventing the opening of cPA to produce lysophosphatidic acid (LPA).
3 Palmitoleoyl 3-
carbacyclic phosphatidic acid (3-
ccPA 16:1) is a cyclic LPA analog that contains the 16:1 fatty acid, palmitoleate, at the
sn-
1 position of the glycerol backbone.
3 At 25 μM, it inhibits the transcellular migration of MM1 cells across mesothelial cell monolayers in response to fetal bovine serum (86.9%) or LPA (99.9%) without affecting proliferation.
3 3-
ccPA 16:1 significantly inhibits autotaxin (IC
50 = 620 nM),
4 an enzyme that is important in cancer cell survival, growth, migration, invasion and metastasis. When delivered intraperitoneally, 3-
ccPA 16:1 significantly reduces the number of lung metastases formed in mice injected with B16F10 melanoma cells in the tail vein.
4
References
1. Kobayashi, T., Tanaka-Ishii, R., Taguchi, R., et al.
Existence of a bioactive lipid, cyclic phosphatidic acid, bound to human serum albumin Life Sci. 65(21),2185-2191(1999).
2. Mukai, M., Imamura, F., Ayaki, M., et al.
Inhibition of tumor invasion and metastasis by a novel lysophosphatidic acid (cyclic LPA) Int. J. Cancer 81,918-922(1999).
3. Uchiyama, A., Mukai, M., Fujiwara, Y., et al.
Inhibition of transcellular tumor cell migration and metastasis by novel carba-derivatives of cyclic phosphatidic acid Biochim. Biophys. Acta 1771,103-112(2007).
4. Baker, D.L., Fujiwara, Y., Pigg, K.R., et al.
Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis J. Biol. Chem. 281(32),22786-22793(2006).
