Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells
Inhibition of 5-lipoxygenase by MK886 augments the antitumor activity of celecoxib in human colon cancer cells
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DOI：
10.1158/1535-7163.mct-06-0318
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发表时间：
2006-11-01
影响因子：
5.7
通讯作者：
Masini, Emanuela
中科院分区：
文献类型：
--
作者：
Cianchi, Fabio;Cortesini, Camillo;Masini, Emanuela
环氧合酶 (COX)-2 和 5-脂氧合酶 (5-LOX) 是参与花生四烯酸代谢的关键酶。他们的产品前列腺素和白三烯与结直肠肿瘤的发展有关。我们的目的是评估联合阻断 COX-2 和 5-LOX 通路是否可能对结直肠癌产生附加的抗肿瘤作用。在 24 份人类结直肠癌样本中评估了 COX-2 和 5-LOX 的表达/活性。在 Caco-2 和 HT29 结肠癌细胞中评估了 COX-2 抑制剂塞来昔布和 5-LOX 抑制剂 MK886 对前列腺素 E-2 和半胱氨酰白三烯产生、肿瘤细胞增殖、细胞凋亡和 Bcl-2/Bax 表达的影响。我们还研究了酶抑制对线粒体膜去极化的影响，线粒体膜去极化是神经酰胺诱导细胞凋亡的最重要机制之一。与正常结肠粘膜相比，肿瘤组织中发现 COX-2 和 5-LOX 通路上调。单独抑制 COX-2 或 5-LOX 会导致结肠癌细胞中另一条途径的激活。 10 μmol/L塞来昔布和MK886联合治疗可以阻止这种激活，与单独使用任一抑制剂治疗相比，在抑制肿瘤细胞增殖、诱导细胞凋亡、降低Bcl-2表达、增加Bax表达和确定线粒体去极化方面具有累加效应。给予神经酰胺合酶抑制剂伏马菌素 1311 可以预防其中一些抗肿瘤作用。总之，我们的研究表明，MK886 抑制 5-LOX 可以增强塞来昔布对人结直肠癌的抗肿瘤活性。
Cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LOX) are key enzymes involved in arachidonic acid metabolism. Their products, prostaglandins and leukotrienes, are involved in colorectal tumor development. We aimed at evaluating whether combined blocking of the COX-2 and 5-LOX pathways might have additive antitumor effects in colorectal cancer. The expression/activity of COX-2 and 5-LOX were assessed in 24 human colorectal cancer specimens. The effects of the COX-2 inhibitor celecoxib and the 5-LOX inhibitor MK886 on prostaglandin E-2 and cysteinyl leukotriene production, tumor cell proliferation, cell apoptosis, and Bcl-2/Bax expression were evaluated in the Caco-2 and HT29 colon cancer cells. We also investigated the effect of the enzymatic inhibition on mitochondrial membrane depolarization, one of the most important mechanisms involved in ceramide-induced apoptosis. Up-regulation of the COX-2 and 5-LOX pathways was found in the tumor tissue in comparison with normal colon mucosa. Inhibition of either COX-2 or 5-LOX alone resulted in activation of the other pathway in colon cancer cells. Combined treatment with 10 mu mol/L celecoxib and MK886 could prevent this activation and had additive effects on inhibiting tumor cell proliferation, inducing cell apoptosis, decreasing Bcl-2 expression, increasing Bax expression, and determining mitochondrial depolarization in comparison with treatment with either inhibitor alone. The administration of the ceramide synthase inhibitor fumonisin 1311 could prevent some of these antineoplastic effects. In conclusion, our study showed that inhibition of 5-LOX by MK886 could augment the antitumor activity of celecoxib in human colorectal cancer.