Resveratrol, a red wine polyphenol, suppresses pancreatic cancer by inhibiting leukotriene A₄ hydrolase

The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxytrans-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 A₄ hydrolase (LTA₄H) as a relevant target in pancreatic cancer. LTA₄H knockdown limited the formation of leukotriene B₄ (LTB₄), the enzymatic product of LTA₄H, and suppressed anchorage-independent growth of pancreatic cancer cells. An in silico shape similarity algorithm predicted that LTA₄H might be a potential target of resveratrol. In support of this idea, we found that resveratrol directly bound to LTA ₄H in vitro and in cells and suppressed proliferation and anchorage-independent growth of pancreatic cancer by inhibiting LTB₄ production and expression of the LTB₄ receptor 1 (BLT₁). Notably, resveratrol exerted relatively stronger inhibitory effects than bestatin, an established inhibitor of LTA₄H activity, and the inhibitory effects of resveratrol were reduced in cells where LTA₄H was suppressed by shRNA-mediated knockdown. Importantly, resveratrol inhibited tumor formation in a xenograft mouse model of human pancreatic cancer by inhibiting LTA₄H activity. Our findings identify LTA₄H as a functionally important target for mediating the anticancer properties of resveratrol.