Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol
Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol
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DOI：
10.1016/j.bcp.2009.02.005
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发表时间：
2009-05-01
影响因子：
5.8
通讯作者：
Werz, Oliver
中科院分区：
文献类型：
--
作者：
Koeberle, Andreas;Northoff, Hinnak;Werz, Oliver
Guttiferae种果皮中的Garcinol（camboginol）具有抗癌和抗炎特性，但其潜在的分子机制尚不清楚。在这里，我们表明，garcinol有效地干扰5-脂氧合酶（EC 7.13.11.34）和微粒体前列腺素（PG）E-2合酶（mPGES）-1（EC 5.3.99.3），酶在炎症和肿瘤发生中发挥关键作用。在无细胞试验中，Garcinol抑制纯化的5-脂氧合酶的活性，并阻断mPGES-1介导的PGH（2）向PCE 2的转化，IC 50值分别为0.1和0.3 μ M。Garcinol还抑制了完整的人中性粒细胞中5-脂氧合酶产物的形成，并减少了白细胞介素-1 β刺激的A549人肺癌细胞以及脂多糖刺激的人全血中PGE（2）的形成。此外，Garcinol干扰人血小板中分离的环氧合酶（考克斯）-1（EC 1.14.99.1，IC 50 = 12 μ M）和考克斯-1衍生的12（S）-羟基-5-顺式-8，10-反式-十七碳三烯酸和血栓烷B-2的形成。相反，钙离子载体（A23187）诱导的中性粒细胞中花生四烯酸释放和A549细胞或全血中考克斯-2活性（以6-酮PGF（1 α）的形成测定）或分离的人重组考克斯-2均未受到Garcinol（
Garcinol (camboginol) from the fruit rind of Guttiferae species shows anti-carcinogenic and and inflammatory properties, but the underlying molecular mechanisms are unclear. Here we show that garcinol potently interferes with 5-lipoxygenase (EC 7.13.11.34) and microsomal prostaglandin (PG)E-2 synthase (mPGES)-1 (EC 5.3.99.3), enzymes that play pivotal roles in inflammation and tumorigenesis. In cell-free assays, garcinol inhibited the activity of purified 5-lipoxygenase and blocked the mPGES-1-mediated conversion of PGH(2) to PCE2 with IC50 values of 0.1 and 0.3 mu M, respectively. Garcinol suppressed 5-lipoxygenase product formation also in intact human neutrophils and reduced PGE(2) formation in interleukin-1 beta-stimulated A549 human lung carcinoma cells as well as in human whole blood stimulated by lipopolysaccharide. Moreover, garcinol interfered with isolated cyclooxygenase (COX)-1 (EC 1.14.99.1, IC50 = 12 mu M) and with the formation of COX-1-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid and thromboxane B-2 in human platelets. In contrast, neither Ca2+-ionophore (A23187)-induced arachidonic acid release in neutrophils nor COX-2 activity in A549 cells or whole blood, measured as formation of 6-keto PGF(1 alpha), or isolated human recombinant COX-2 were significantly affected by garcinol (