Resveratrol prevents apoptosis in K562 cells by inhibiting lipoxygenase and cyclooxygenase activity

Abstract

The natural polyphenolic compound resveratrol (trans-3,4 H ,5-trihydroxystilbene) is shown to prevent apoptosis (programmed cell death) induced in human erythroleukemia K562 cells by hydrogen peroxide and other unrelated stimuli. Resveratrol reversed the elevation of leukotriene B 4 (from 6.40^0.65 to 2.92^0.30 pmol´mg protein 21 ) and prostaglandin E 2 (from 11.46^1.15 to 8.02^0.80 nmol´mg protein 21 ), induced by H 2 O 2 challenge in K562 cells. The reduction of leukotriene B 4 and prostaglandin E 2 correlated with the inhibition of the 5-lipoxygenase activity, and the cyclooxygenase and peroxidase activity of prostaglandin H synthase, respectively. Resveratrol also blocked lipoperoxidation induced by hydrogen peroxide in K562 cell membranes. Resveratrol was found to act as a competitive inhibitor of purified 5-lipoxygenase and 15-lipoxygenase and prostaglandin H synthase, with inhibition constants of 4.5^0.5 mm (5-lipoxygenase), 40^5.0 mm (15-lipoxygenase), 35^4.0 mm (cyclooxygenase activity of prostaglandin H synthase) and 30^3.0 mm (peroxidase activity of prostaglandin H synthase). Altogether, the results reported here suggest that the anti-apoptotic activity of resveratrol depends on the direct inhibition of the main arachidonate-metabolizing enzymes.Keywords: apoptosis; cyclooxygenase; lipoxygenase; oxidative stress; resveratrol.Resveratrol (trans-3,4 H ,5-trihydroxystilbene) occurs naturally in grapes and a variety of medicinal plants, where it functions as a phytoalexin that protects against infections and other stress factors [1]. Because of its high concentration in grape skin, a significant amount of resveratrol is present in red wine [2] and is thought to be responsible for the reduced risk of cardiovascular disease associated with moderate consumption of this beverage [2]. Resveratrol has been reported to have antiplatelet [1], anti-inflammatory [3,4] and anticarcinogenic [5] effects. Recently, it has also been reported to act as an agonist for the estrogen receptor [6] and to inhibit phorbolester-mediated activation of protein kinase C and AP-1-mediated gene expression in human mammary epithelial cells [7]. The various activities of resveratrol have been attributed to its antioxidant properties [8], which contribute to control the intracellular redox balance by inhibiting the formation of reactive oxygen species (ROS; [5]). Moreover, this polyphenolic compound interferes with the arachidonate metabolism, by reducing the levels of leukotrienes (generated by the`l ipoxygenase pathway' of the arachidonate cascade) and prostanoids (generated by the`cyclooxygenase pathway'), and this activity is also considered crucial for its biological effects [3,5,7]. Although the cyclooxygenase activity [5] and expression [7] of prostaglandin H synthase (PHS) have been shown to be reduced by resveratrol in cellular systems, a direct interaction of this compound with the enzyme has not been characterized to date. The effect of resveratrol on the other arachidonate-metabolizing enzyme, lipoxygenase, has not been inve...

The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production

“…Preliminary observations from our group indicate that LTB 4 exerts catabolic activities on articular chondrocytes by decreasing matrix synthesis, which suggests that LTB 4 has a pathologic role in OA; however, relatively little is known about its effects on cartilage metabolism (35). Although the mechanism of resveratrolmediated inhibition of LTB 4 was not investigated in our study, it has been shown that resveratrol can also act as a potent inhibitor of the dioxygenase activity of LOX (36), the cell source of LTB 4 .…”

Lipoxygenases and their involvement in programmed cell death

“…7 Resveratrol, an alleged natural cancer preventive agent present in red wine, 40 has been shown to inhibit PCD induced by unrelated stimuli in human erythroleukemia K562 cells, through competitive inhibition of 5-LOX and 15-LOX activity. 41 However, resveratrol is a general antioxidant which also inhibits nonenzymatic lipoperoxidation and cyclooxygenase activity 41 and acts as an agonist for the estrogen receptor. 42 Finally caffeic acid, which prevents apoptosis linked to 5-LOX activation, 15 is a LOX inhibitor with general antioxidant properties, 43 much like the 5-LOX inhibitor atocopherol.…”

Anti-atherogenic effects of resveratrol

“…In rat liver microsomes, RS inhibited iron-induced as well as ultraviolet-irradiated lipid peroxidation and prevented LDL oxidation by copper (Fauconneau et al, 1997;Miura et al, 2000). RS could effectively prevent oxidative LDL modification by inhibiting lipoxygenase enzyme activity (Maccarrone et al, 1999;Kovanen and Pentikäinen, 2003). Polyphenols in red wine including RS have been reported to inhibit LDL oxidation; this effect was found to be stronger than the well-known anti-oxidant a-tocopherol .…”