TY - JOUR
T1 - In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment
AU - Quesada, A. J.
AU - Nelius, T.
AU - Yap, R.
AU - Zaichuk, T. A.
AU - Alfranca, A.
AU - Filleur, S.
AU - Volpert, Olga V.
AU - Redondo, J. M.
N1 - Funding Information:
This work has been supported by ACS Grant RSG-01-099-01-CSM (OV), NIH grant RO1 HL68003-01 and an award from Abbott Laboratories (OV). JMR was supported by FIS Grant 01/218 and RECAVA from Ministerio de Sanidad y Consumo of Spain and SAF 2003-02920 from DGI , MCYT. AJQ is holder of a FPI fellowship from Ministerio de Ciencia y Tecnología of Spain. AA is supported by a CNIC grant. We are grateful to Drs Zhou Wang (Northwestern University) and Abelardo López-Rivas (Instituto de Parasitología y Biomedicina) for helpful discussion. We want to thank Pilar Torralbo and Alberto Álvarez from CNIC Flow Cytometry Facility.
PY - 2005/6
Y1 - 2005/6
N2 - 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-DlTSP 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.
AB - 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-DlTSP 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.
KW - Antiangiogenesis by thrombospondin-1
KW - CD95 and CD95L
KW - Drug optimization by design
KW - Endothelial cell apoptosis
KW - Primary and secondary receptors
KW - Synergy with doxorubicin
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U2 - 10.1038/sj.cdd.4401615
DO - 10.1038/sj.cdd.4401615
M3 - Article
C2 - 15818399
AN - SCOPUS:20044376571
SN - 1350-9047
VL - 12
SP - 649
EP - 658
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 6
ER -