Differential effects of ABT-510 and a CD36-binding peptide derived from the type 1 repeats of thrombospondin-1 on fatty acid uptake, nitric oxide signaling, and caspase activation in vascular cells.
ABT-510 is a potent mimetic of an anti-angiogenic sequence from the second type 1 repeat of thrombospondin-1. ABT-510 and the original d-Ile mimetic from which it was derived, GDGV(dI)TRIR, are similarly active for inhibiting vascular outgrowth in a B16 melanoma explant assay. Because GDGV(dI)TRIR and thrombospondin-1 modulate nitric oxide signaling by inhibiting the fatty translocase activity of CD36, we examined the ability ABT-510 to modulate fatty acid uptake into vascular cells and downstream nitric oxide/cGMP signaling. Remarkably, ABT-510 is less active than GDGV(dI)TRIR for inhibiting myristic acid uptake into both endothelial and vascular smooth muscle cells. Correspondingly, ABT-510 is less potent than GDGV(dI)TRIR for blocking a myristate-stimulated increase in cell adhesion to collagen and nitric oxide-driven accumulation of cGMP. ABT-510 at concentrations sufficient to inhibit CD36 fatty acid translocase activity synergizes with thrombin in aggregating platelets and blunts the activity of NO to delay aggregation, but again less than GDGV(dI)TRIR. In contrast, ABT-510 is more potent than GDGV(dI)TRIR for inducing caspase activation in vascular cells. Thus, we propose that ABT-510 is a drug with at least two mechanisms of action, and its potent anti-tumor activity may be in part independent of CD36 fatty acid translocase inhibition.
Isenberg
Jeff S
JS
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Yu
Christine
C
Roberts
David D
DD
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D009842:Oligopeptides / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; D018955:CD36 Antigens; D005227:Fatty Acids; C500617:NAc-Sar-Gly-Val-(d-allo-Ile)-Thr-Nva-Ile-Arg-ProNEt; D009842:Oligopeptides; D019700:Thrombospondin 1; D009569:Nitric Oxide; D020169:Caspases; D006152:Cyclic GMP