The immunosuppressant FTY720 inhibits tumor angiogenesis via the sphingosine 1-phosphate receptor 1.
FTY720, a sphingosine 1-phosphate (S1P) analog, acts as an immunosuppressant through trapping of T cells in secondary lymphoid tissues. FTY720 was also shown to prevent tumor growth and to inhibit vascular permeability. The MTT proliferation assay illustrated that endothelial cells are more susceptible to the anti-proliferative effect of FTY720 than Lewis lung carcinoma (LLC1) cells. In a spheroid angiogenesis model, FTY720 potently inhibited the sprouting activity of VEGF-A-stimulated endothelial cells even at concentrations that apparently had no anti-proliferative effect. Mechanistically, the anti-angiogenic effect of the general S1P receptor agonist FTY720 was mimicked by the specific S1P1 receptor agonist SEW2871. Moreover, the anti-angiogenic effect of FTY720 was abrogated in the presence of CXCR4-neutralizing antibodies. This indicates that the effect was at least in part mediated by the S1P1 receptor and involved transactivation of the CXCR4 chemokine receptor. Additionally, we could illustrate in a coculture spheroid model, employing endothelial and smooth muscle cells (SMCs), that the latter confer a strong protective effect regarding the action of FTY720 upon the endothelial cells. In a subcutaneous LLC1 tumor model, the anti-angiogenic capacity translated into a reduced tumor size in syngeneic C57BL/6 mice. Consistently, in the Matrigel plug in vivo assay, 10 mg/kg/d FTY720 resulted in a strong inhibition of angiogenesis as demonstrated by a reduced capillary density. Thus, in organ transplant patients, FTY720 may prove efficacious in preventing graft rejection as well as tumor development.
Schmid
Gerald
G
Department of Surgery, Ludwig-Maximilian University, Klinikum Grosshadern, Munich, Germany.
Guba
Markus
M
Ischenko
Ivan
I
Papyan
Armine
A
Joka
Mareile
M
Schrepfer
Sabine
S
Bruns
Christiane J
CJ
Jauch
Karl-Walter
KW
Heeschen
Christopher
C
Graeb
Christian
C
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000187:drug effects; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007797:Laminin / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009500:Neutralization Tests; D010069:Oxadiazoles / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology*; D011509:Proteoglycans / Q000187:drug effects; D019718:Receptors, CXCR4 / Q000097:blood; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D015533:Transcriptional Activation; D014185:Transplantation, Isogeneic; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; C514936:CXCR4 protein, mouse; D004338:Drug Combinations; D007166:Immunosuppressive Agents; D007797:Laminin; D010069:Oxadiazoles; D011409:Propylene Glycols; D011509:Proteoglycans; D019718:Receptors, CXCR4; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine