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.
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Abbreviations
- TSP1:
-
thrombospondin-1
- DXR:
-
doxorubicin
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Acknowledgements
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.
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Quesada, A., Nelius, T., Yap, R. et al. In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment. Cell Death Differ 12, 649–658 (2005). https://doi.org/10.1038/sj.cdd.4401615
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DOI: https://doi.org/10.1038/sj.cdd.4401615
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