In vivo upregulation of CD95 and CD95L causes synergistic inhibition of angiogenesis by TSP1 peptide and metronomic doxorubicin treatment

A. J. Quesada, T. Nelius, R. Yap, T. A. Zaichuk, A. Alfranca, S. Filleur, Olga V. Volpert*, J. M. Redondo

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)649-658
Number of pages10
JournalCell Death and Differentiation
Volume12
Issue number6
DOIs
StatePublished - Jun 2005

Keywords

  • Antiangiogenesis by thrombospondin-1
  • CD95 and CD95L
  • Drug optimization by design
  • Endothelial cell apoptosis
  • Primary and secondary receptors
  • Synergy with doxorubicin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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