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

• Published in: Molecular cancer research Vol. 2; no. 10; pp. 541 - 550
• Main Authors: Huang, Hanhua, Campbell, Steven C, Bedford, Dhugal F, Nelius, Thomas, Veliceasa, Dorina, Shroff, Emelyn H, Henkin, Jack, Schneider, Andrew, Bouck, Noel, Volpert, Olga V
• Format: Journal Article
• Language: English
• Published: United States 01.10.2004
• Subjects: Angiogenesis Inhibitors - pharmacology; CD36 Antigens - metabolism; Cells, Cultured; Chromans - pharmacology; Drug Interactions; Endothelium, Vascular - cytology; Humans; Ligands; Microcirculation; Neoplasms - blood supply; Neoplasms - drug therapy; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Peptides - pharmacology; PPAR gamma - metabolism; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; Thiazolidinediones - pharmacology; Thrombospondin 1 - pharmacology; Vasodilator Agents - pharmacology
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.541.2.10

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 gamma (PPARgamma), 15-deoxy-delta(12,14)-prostaglandin J2, troglitazone, and rosiglitazone increased PPARgamma and CD36 expression in endothelial cells and improved the efficacy of TSP1 and ABT510 in a CD36-dependent manner. The ABT510 and PPARgamma ligands cooperatively blocked angiogenic endothelial functions in vitro and neovascularization in vivo. In tumor xenografts, 15-deoxy-delta(12,14)-prostaglandin J2 and troglitazone synergistically improved antiangiogenic and antitumor effects of ABT510. Our data provide one mechanism for the in vivo angioinhibitory effect of PPARgamma ligands and show fine-tuning of the antiangiogenic efficacy via targeted up-regulation of the endothelial receptor.