Tumor angiogenesis suppression by alpha-eleostearic acid, a linolenic acid isomer with a conjugated triene system, via peroxisome proliferator-activated receptor gamma.

We have shown previously that alpha-eleostearic acid (ESA), a linolenic acid isomer with a conjugated triene system, suppresses tumor growth in vivo. In our earlier study, blood vessels were observed at the tumor surface in control mice, whereas in ESA-treated mice no such vessels were observed and the inner part of the tumor was discolored. These observations suggested that ESA might suppress cancer cell growth through malnutrition via a suppressive effect on tumor angiogenesis. In the current study, the antiangiogenic effects of ESA were investigated in vivo and in vitro. Tumor cell-induced vessel formation was clearly suppressed in mice orally administered ESA at doses of 50 and 100 mg/kg/day in a dose-dependent manner. ESA also inhibited the formation of capillary-like networks by human umbilical vein endothelial cells (HUVEC) and moderately inhibited HUVEC proliferation and migration in a dose-dependent manner. The mechanism by which ESA inhibited angiogenesis was through suppression of the expression of vascular endothelial growth factor receptors 1 and 2, activation of peroxisome proliferator-activated receptor gamma (PPARgamma) and induction of apoptosis in HUVEC. We thus demonstrated that, like troglitazone, ESA is a PPARgamma ligand and that it activates PPARgamma, induces apoptosis in HUVEC and inhibits angiogenesis. Our findings suggest that ESA has potential use as a therapeutic dietary supplement and medicine for minimizing tumor angiogenesis.