Carcinogenesis Advance Access originally published online on January 3, 2008
Carcinogenesis 2008 29(4):797-806; doi:10.1093/carcin/bgm298
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Tumor angiogenesis suppression by 
-eleostearic acid, a linolenic acid isomer with a conjugated triene system, via peroxisome proliferator-activated receptor 
Laboratory of Biodynamic Chemistry, School of Food, Agricultural and Environment Sciences, Miyagi University, Sendai 982-0215, Japan
1 Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, 111 Kuboki, Soja, Okayama 719-1197, Japan
* To whom correspondence should be addressed. Tel: +81 22 245 1382; Fax: +81 22 245 1534; Email: tsuduki{at}myu.ac.jp
We have shown previously that 
-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 
(PPAR) and induction of apoptosis in HUVEC. We thus demonstrated that, like troglitazone, ESA is a PPAR ligand and that it activates PPAR, 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.
Abbreviations: CLA, conjugated linoleic acid; CLA-TG, the triacylglycerol form of CLA prepared from high-linoleic safflower oil; ESA, -eleostearic acid; FBS, fetal bovine serum; GW, GW9662; HUVEC, human umbilical vein endothelial cells; LA, linoleic acid; LNA, -linolenic acid; RT–PCR, reverse transcriptase polymerase chain reaction; PPAR, peroxisome proliferator-activated receptor ; VEGF, vascular endothelial growth factor; VEGF-R1, VEGF receptor 1; VEGF-R2, VEGF receptor 2; WST-1, 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate sodium salt
Received October 31, 2007; revised December 16, 2007; accepted December 16, 2007.