Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, CD / metabolism
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Apoptosis / drug effects
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CD47 Antigen
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Cells, Cultured
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Disease Progression
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Doxorubicin / pharmacology*
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Drug Synergism
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Fas Ligand Protein
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Humans
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Membrane Glycoproteins / metabolism*
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Mice
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Neoplasms / blood supply
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Neoplasms / metabolism
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Neoplasms / pathology
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Neovascularization, Pathologic / drug therapy*
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Peptide Fragments / pharmacology
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Thrombospondin 1 / chemistry
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Thrombospondin 1 / pharmacology*
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Tumor Suppressor Protein p53 / metabolism
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Umbilical Cord / cytology
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Umbilical Cord / drug effects
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Umbilical Cord / metabolism
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Up-Regulation / drug effects*
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Xenograft Model Antitumor Assays
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fas Receptor / metabolism*
Substances
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Antigens, CD
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CD47 Antigen
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CD47 protein, human
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Cd47 protein, mouse
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Membrane Glycoproteins
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Peptide Fragments
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Thrombospondin 1
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Tumor Suppressor Protein p53
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fas Receptor
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Doxorubicin