Antagonism of sphingosine-1-phosphate receptors by FTY720 inhibits angiogenesis and tumor vascularization.
FTY720, a potent immunomodulator, becomes phosphorylated in vivo (FTY-P) and interacts with sphingosine-1-phosphate (S1P) receptors. Recent studies showed that FTY-P affects vascular endothelial growth factor (VEGF)-induced vascular permeability, an important aspect of angiogenesis. We show here that FTY720 has antiangiogenic activity, potently abrogating VEGF- and S1P-induced angiogenesis in vivo in growth factor implant and corneal models. FTY720 administration tended to inhibit primary and significantly inhibited metastatic tumor growth in a mouse model of melanoma growth. In combination with a VEGFR tyrosine kinase inhibitor PTK787/ZK222584, FTY720 showed some additional benefit. FTY720 markedly inhibited tumor-associated angiogenesis, and this was accompanied by decreased tumor cell proliferation and increased apoptosis. In transfected HEK293 cells, FTY-P internalized S1P1 receptors, inhibited their recycling to the cell surface, and desensitized S1P receptor function. Both FTY720 and FTY-P apparently failed to impede VEGF-produced increases in mitogen-activated protein kinase activity in human umbilical vascular endothelial cells (HUVEC), and unlike its activity in causing S1PR internalization, FTY-P did not result in a decrease of surface VEGFR2 levels in HUVEC cells. Pretreatment with FTY720 or FTY-P prevented S1P-induced Ca2+ mobilization and migration in vascular endothelial cells. These data show that functional antagonism of vascular S1P receptors by FTY720 potently inhibits angiogenesis; therefore, this may provide a novel therapeutic approach for pathologic conditions with dysregulated angiogenesis.
LaMontagne
Kenneth
K
Novartis Institutes for BioMedical Research, East Hanover, New Jersey, USA.
Littlewood-Evans
Amanda
A
Schnell
Christian
C
O'Reilly
Terence
T
Wyder
Lorenza
L
Sanchez
Teresa
T
Probst
Beatrice
B
Butler
Jeannene
J
Wood
Alexander
A
Liau
Gene
G
Billy
Eric
E
Theuer
Andreas
A
Hla
Timothy
T
Wood
Jeanette
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003315:Cornea / Q000098:blood supply; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010766:Phosphorylation; D010793:Phthalazines / Q000494:pharmacology; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D010793:Phthalazines; D011409:Propylene Glycols; D011725:Pyridines; D049349:Receptors, Lysosphingolipid; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib; D040301:Vascular Endothelial Growth Factor Receptor-2; D020928:Mitogen-Activated Protein Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D002118:Calcium