Resveratrol, a Red Wine Polyphenol, Suppresses Pancreatic Cancer by Inhibiting Leukotriene A4 Hydrolase

Abstract

The anticancer effects of red wine have attracted considerable attention. Resveratrol (3,5,4′-trihydroxy-trans-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 LTA4H 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.

Resveratrol Inhibits Proliferation and Induces Apoptosis through the Hedgehog Signaling Pathway in Pancreatic Cancer Cell

“…Over the past couple of decades, after Jang et al [16] reported Res as a cancer chemopreventive agent, it has received tremendous attention. Recent studies have shown its anticancer effects on pancreatic carcinoma [17,18,19]. However, the mechanism has not been well known.…”

Evaluating the in silico activity of bioactive compound iressa, tarceva and capsaicin against epidermal growth factor receptor tyrosine kinase

“…Scoring estimates the chemical interactions, such as binding strength and energy state, between the ligand and protein to assist in the in ranking the efficacy of the compound being scored (Nagarajan et al, 2009;Perez-Sanchez and Wenzel, 2011;Oi et al, 2010). From these approaches, several potential candidate phytochemicals that directly interact with target proteins can be identified in future for the development of effective drug against cancer.…”

Recent advances in pancreatic cancer: biology, treatment, and prevention

“…Additionally, resveratrol has been found to suppress proliferation and anchorage-independent growth of pancreatic cancer by inhibiting leukotriene B4 (LTB4) production and expression of the LTB4 receptor 1 (LTB4R1) [146]. It is remarkable that LTB4 is a hydrolysis product of the leukotriene A4 (LTA4), and the process is catalyzed by LTA4 hydrolase, a known target for prevention and therapy of cancers including PC [147].…”

“…It is remarkable that LTB4 is a hydrolysis product of the leukotriene A4 (LTA4), and the process is catalyzed by LTA4 hydrolase, a known target for prevention and therapy of cancers including PC [147]. Resveratrol can directly bind to leukotriene A4 hydrolase (LTA-4H) and inhibit its activity and, therefore, LTB4 production [146].…”