Peroxisome proliferator-activated receptor gamma ligands improve the antitumor efficacy of thrombospondin peptide ABT510.
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.
Huang
Hanhua
H
Department of Urology, Northwestern University Medical School, Chicago, IL 60611, USA.
Campbell
Steven C
SC
Bedford
Dhugal F
DF
Nelius
Thomas
T
Veliceasa
Dorina
D
Shroff
Emelyn H
EH
Henkin
Jack
J
Schneider
Andrew
A
Bouck
Noel
N
Volpert
Olga V
OV
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D018955:CD36 Antigens / Q000378:metabolism; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D004347:Drug Interactions; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D008024:Ligands; D008833:Microcirculation; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000494:pharmacology*; D000077288:Troglitazone; D014665:Vasodilator Agents / Q000494:pharmacology
C477819:15-deoxyprostaglandin J2; D020533:Angiogenesis Inhibitors; D018955:CD36 Antigens; D002839:Chromans; D008024:Ligands; D047495:PPAR gamma; D010455:Peptides; D045162:Thiazolidinediones; D019700:Thrombospondin 1; D014665:Vasodilator Agents; D000077288:Troglitazone; D015230:Prostaglandin D2