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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Female
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Humans
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Lysophospholipids / blood
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Mice
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Mice, Inbred C57BL
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Multienzyme Complexes / antagonists & inhibitors*
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Multienzyme Complexes / metabolism
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Neoplasm Metastasis
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Neovascularization, Pathologic
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Organophosphates / chemistry
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Organophosphates / pharmacology*
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Phosphodiesterase I / antagonists & inhibitors*
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Phosphodiesterase I / metabolism
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Phosphodiesterase Inhibitors / chemistry
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Phosphodiesterase Inhibitors / pharmacology*
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Phosphoric Diester Hydrolases / metabolism*
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Pyrophosphatases / antagonists & inhibitors*
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Pyrophosphatases / metabolism
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Sphingosine / analogs & derivatives*
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Sphingosine / chemistry
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Sphingosine / pharmacology
Substances
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Antineoplastic Agents
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FTY 720P
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Lysophospholipids
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Multienzyme Complexes
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Organophosphates
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Phosphodiesterase Inhibitors
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Phosphoric Diester Hydrolases
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Phosphodiesterase I
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alkylglycerophosphoethanolamine phosphodiesterase
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Pyrophosphatases
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Sphingosine
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lysophosphatidic acid