Data from Resveratrol, a Red Wine Polyphenol, Suppresses Pancreatic Cancer by Inhibiting Leukotriene A<sub>4</sub> Hydrolase

Abstract

<div>Abstract<p>The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy-<i>trans</i> -stilbene) is a well-known polyphenolic compound of red wine with cancer chemopreventive activity. However, the basis for this activity is unclear. We studied leukotriene A<sub>4</sub> hydrolase (LTA<sub>4</sub>H) as a relevant target in pancreatic cancer. LTA<sub>4</sub>H knockdown limited the formation of leukotriene B<sub>4</sub> (LTB<sub>4</sub>), the enzymatic product of LTA<sub>4</sub>H, and suppressed anchorage-independent growth of pancreatic cancer cells. An <i>in silico</i> shape similarity algorithm predicted that LTA<sub>4</sub>H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA<sub>4</sub>H <i>in vitro</i> and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB<sub>4</sub> production and expression of the LTB<sub>4</sub> receptor 1 (BLT<sub>1</sub>). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA<sub>4</sub>H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA<sub>4</sub>H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA<sub>4</sub>H activity. Our findings identify LTA<sub>4</sub>H as a functionally important target for mediating the anticancer properties of resveratrol. <i>Cancer Res; 70(23); 9755–64. ©2010 AACR</i>.</p></div>