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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.
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https://www.hal.inserm.fr/inserm-00409422
Contributor : Marie Francoise Simon <>
Submitted on : Friday, August 7, 2009 - 3:49:05 PM
Last modification on : Friday, January 10, 2020 - 9:09:09 PM

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Laurens van Meeteren, Volker Brinkmann, Jean Sébastien Saulnier-Blache, Kevin Lynch, Wouter Moolenaar. Anticancer activity of FTY720: phosphorylated FTY720 inhibits autotaxin, a metastasis-enhancing and angiogenic lysophospholipase D.. Cancer Letters, Elsevier, 2008, 266 (2), pp.203-8. ⟨10.1016/j.canlet.2008.02.052⟩. ⟨inserm-00409422⟩

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