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

Laurens A van Meeteren1, Volker Brinkmann, Jean Sébastien Saulnier-Blache

  • 1Division of Cellular Biochemistry and Center for Biomedical Genetics, The Netherlands Cancer Institute, 1066 Amsterdam, The Netherlands.

Cancer Letters
|April 2, 2008
PubMed

Insights

FTY720, an immunomodulator, inhibits tumor progression by targeting autotaxin (ATX). This drug reduces lysophosphatidic acid (LPA) levels, suggesting a novel anticancer mechanism via the ATX-LPA axis.

Area of Science:

  • Oncology
  • Pharmacology
  • Biochemistry

Background:

  • FTY720 is an established immunomodulator targeting sphingosine 1-phosphate receptors.
  • At higher doses, FTY720 exhibits anticancer effects via an uncharacterized mechanism.
  • Autotaxin (ATX) is implicated in cancer metastasis and angiogenesis through lysophosphatidic acid (LPA) production.

Purpose of the Study:

  • To elucidate the mechanism by which FTY720 inhibits tumor progression.
  • To investigate FTY720-phosphate's interaction with autotaxin (ATX).
  • To assess the impact of FTY720 on plasma lysophosphatidic acid (LPA) levels in vivo.

Main Methods:

  • In vitro enzymatic assays to determine FTY720-phosphate's inhibitory activity against ATX.
  • Comparison of FTY720-phosphate's effect on ATX versus its homolog NPP1.
  • In vivo pharmacokinetic study in mice administering FTY720 orally and measuring plasma LPA levels.

Main Results:

  • FTY720-phosphate competitively inhibits autotaxin (ATX) with a Ki of approximately 0.2 microM.
  • FTY720-phosphate did not inhibit the closely related enzyme NPP1.
  • Oral administration of FTY720 (3 mg/kg) in mice significantly decreased plasma LPA levels.

Conclusions:

  • FTY720-phosphate directly targets and inhibits autotaxin (ATX).
  • The inhibition of ATX by FTY720-phosphate leads to reduced LPA production.
  • These findings suggest the ATX-LPA axis is a key mediator of FTY720's anticancer effects.

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