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.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2005 |
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| Erschienen: |
2005 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
|---|---|
| Enthalten in: |
Cell death and differentiation - 12(2005), 6 vom: 15. Juni, Seite 649-58 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Quesada, A J [VerfasserIn] |
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| Anmerkungen: |
Date Completed 06.10.2005 Date Revised 16.11.2017 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM154688320 |
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| 100 | 1 | |a Quesada, A J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment |
| 264 | 1 | |c 2005 | |
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| 500 | |a Date Completed 06.10.2005 | ||
| 500 | |a Date Revised 16.11.2017 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
| 650 | 7 | |a Antigens, CD |2 NLM | |
| 650 | 7 | |a CD47 Antigen |2 NLM | |
| 650 | 7 | |a CD47 protein, human |2 NLM | |
| 650 | 7 | |a Cd47 protein, mouse |2 NLM | |
| 650 | 7 | |a FASLG protein, human |2 NLM | |
| 650 | 7 | |a Fas Ligand Protein |2 NLM | |
| 650 | 7 | |a Fasl protein, mouse |2 NLM | |
| 650 | 7 | |a Membrane Glycoproteins |2 NLM | |
| 650 | 7 | |a Peptide Fragments |2 NLM | |
| 650 | 7 | |a Thrombospondin 1 |2 NLM | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a fas Receptor |2 NLM | |
| 650 | 7 | |a Doxorubicin |2 NLM | |
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| 700 | 1 | |a Nelius, T |e verfasserin |4 aut | |
| 700 | 1 | |a Yap, R |e verfasserin |4 aut | |
| 700 | 1 | |a Zaichuk, T A |e verfasserin |4 aut | |
| 700 | 1 | |a Alfranca, A |e verfasserin |4 aut | |
| 700 | 1 | |a Filleur, S |e verfasserin |4 aut | |
| 700 | 1 | |a Volpert, O V |e verfasserin |4 aut | |
| 700 | 1 | |a Redondo, J M |e verfasserin |4 aut | |
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