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Inhibition of endothelial cell proliferation and angiogenesis by orlistat, a fatty acid synthase inhibitor.

Browne CD, Hindmarsh EJ, Smith JW

Cancer Research Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Rd., La Jolla, CA 92037, USA.

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.

Published 2 October 2006 in FASEB J, 20(12): 2027-35.
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