In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment.
Antiangiogenic thrombospondin-1 (TSP1) induces endothelial cell death via a CD95-mediated cascade. We used this signaling pathway, where CD95/Fas is a rate-limiting intermediate, as a target to optimize the efficacy of TSP1 active peptide, DI-TSP. Like TSP1, DI-TSP upregulated endothelial CD95L in vivo. To modulate CD95 levels, we chose chemotherapy agent doxorubicin (DXR). DXR caused sustained upregulation of CD95 in the activated endothelium at 1/100 of the maximal tolerated dose. DI-TSP and DXR synergistically induced endothelial apoptosis in vitro, and in vivo, in developing murine vessels. Fas decoy, TSP1 receptor antibody and Pifithrin, a p53 inhibitor, severely decreased apoptosis and restored angiogenesis by DXR-DI-TSP combination, evidencing critical roles of CD95 and TSP1. Combined therapy synergistically blocked neovascularization and progression of the bladder and prostate carcinoma. Such informed design of a complex antiangiogenic therapy based on the rate-limiting molecular targets is a novel concept, which may yield new approaches to cancer treatment.
Quesada
A J
AJ
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Facultad de Ciencias, Universidad Autónoma de Madrid, Cantoblanco 28049, Madrid, Spain.
Nelius
T
T
Yap
R
R
Zaichuk
T A
TA
Alfranca
A
A
Filleur
S
S
Volpert
O V
OV
Redondo
J M
JM
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D051928:CD47 Antigen; D002478:Cells, Cultured; D018450:Disease Progression; D004317:Doxorubicin / Q000494:pharmacology*; D004357:Drug Synergism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010446:Peptide Fragments / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D019014:fas Receptor / Q000378:metabolism*
D015703:Antigens, CD; D051928:CD47 Antigen; C497894:CD47 protein, human; C497895:Cd47 protein, mouse; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D019700:Thrombospondin 1; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D004317:Doxorubicin