Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor.
Orlistat, an antiobesity drug, is cytostatic and cytotoxic to tumor cells. The antitumor activity of orlistat can be attributed to its ability to inhibit the thioesterase domain of fatty acid synthase (FAS). The objective of the present study was to test the effect of orlistat on endothelial cell proliferation and angiogenesis. Orlistat inhibits endothelial cell FAS, blocks the synthesis of fatty acids, and prevents endothelial cell proliferation. More significantly, orlistat inhibits human neovascularization in an ex vivo assay, which suggests that it may be useful as an antiangiogenic drug. The mechanism of these effects can be traced to the fact that orlistat prevents the display of the vascular endothelial growth factor (VEGF) receptor (VEGFR2/KDR/Flk1) on the endothelial cell surface. Thus, orlistat is an antiangiogenic agent with a novel mechanism of action.
Browne
Cecille D
CD
Cancer Research Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037, USA.
Hindmarsh
Elizabeth J
EJ
Smith
Jeffrey W
JW
D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D000077403:Orlistat; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology
D007783:Lactones; D000077403:Orlistat; D064429:Fatty Acid Synthases; D040262:Receptors, Vascular Endothelial Growth Factor