Peroxisome proliferator-activated receptor γ ligands improve the antitumor efficacy of thrombospondin peptide ABT510

Hanhua Huang, Steven C. Campbell, Dhugal F. Bedford, Thomas Nelius, Dorina Veliceasa, Emelyn H. Shroff, Jack Henkin, Andrew Schneider, Noel Bouck, Olga V. Volpert*

*Corresponding author for this work

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

An expanding capillary network is critical for several pathologic conditions. In cancer, the decrease of antiangiogenic thrombospondin-1 (TSP1) often enables an angiogenic switch, which can be reversed with exogenous TSP1 or its peptide derivative ABT510. TSP1 acts by inducing endothelial cell apoptosis via signaling cascade initiated at CD36, a TSP1 antiangiogenic receptor. Here, we show that the ligands of nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), 15-deoxy-Δ12,14-prostaglandin J2, troglitazone, and rosiglitazone increased PPARγ and CD36 expression in endothelial cells and improved the efficacy of TSP1 and ABT510 in a CD36-dependent manner. The ABT510 and PPARγ ligands cooperatively blocked angiogenic endothelial functions in vitro and neovascularization in vivo. In tumor xenografts, 15-deoxy-Δ12,14-prostaglandin J2 and troglitazone synergistically improved antiangiogenic and antitumor effects of ABT510. Our data provide one mechanism for the in vivo angioinhibitory effect of PPARγ ligands and show fine-tuning of the antiangiogenic efficacy via targeted up-regulation of the endothelial receptor.

Original languageEnglish (US)
Pages (from-to)541-550
Number of pages10
JournalMolecular Cancer Research
Volume2
Issue number10
StatePublished - Oct 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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