Anticancer activity of FTY720: phosphorylated FTY720 inhibits autotaxin, a metastasis-enhancing and angiogenic lysophospholipase D.

Abstract	FTY720 is an immunomodulator that is phosphorylated in vivo and inhibits lymphocyte mobilization by targeting sphingosine 1-phospate receptors. At doses higher than required for immunomodulation, FTY720 inhibits tumor progression through an unknown mechanism. Here we show that FTY720-phosphate is a competitive inhibitor (Ki approximately 0.2microM) of autotaxin (ATX or NPP2), a nucleotide phosphodiesterase/pyrophosphatase (NPP) that enhances metastasis and angiogenesis and acts as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA). FTY720-phosphate did no affect the activity of NPP1, the closest relative of ATX. After oral administration in mice, FTY720 (3mg/kg) significantly reduced plasma LPA levels. These results suggest that FTY720 may exert its anticancer effects, at least in part, by targeting the ATX-LPA axis.
Authors	Laurens A van Meeteren, Volker Brinkmann, Jean Sébastien Saulnier-Blache, Kevin R Lynch, Wouter H Moolenaar
Journal	Cancer letters (Cancer Lett) Vol. 266 Issue 2 Pg. 203-8 (Aug 08 2008) ISSN: 0304-3835 [Print] Ireland
PMID	18378389 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents FTY 720P Lysophospholipids Multienzyme Complexes Organophosphates Phosphodiesterase Inhibitors Phosphoric Diester Hydrolases Phosphodiesterase I alkylglycerophosphoethanolamine phosphodiesterase Pyrophosphatases Sphingosine lysophosphatidic acid
Topics	Animals Antineoplastic Agents (chemistry, pharmacology) Female Humans Lysophospholipids (blood) Mice Mice, Inbred C57BL Multienzyme Complexes (antagonists & inhibitors, metabolism) Neoplasm Metastasis Neovascularization, Pathologic Organophosphates (chemistry, pharmacology) Phosphodiesterase I (antagonists & inhibitors, metabolism) Phosphodiesterase Inhibitors (chemistry, pharmacology) Phosphoric Diester Hydrolases (metabolism) Pyrophosphatases (antagonists & inhibitors, metabolism) Sphingosine (analogs & derivatives, chemistry, pharmacology)

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