Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation.
Zileuton, 5-lipoxygenase inhibitor, acts as a chemopreventive agent in intestinal polyposis, by modulating polyp and systemic inflammation.
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DOI：
10.1371/journal.pone.0121402
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Bentrem DJ
中科院分区：
文献类型：
--
作者：
Gounaris E;Heiferman MJ;Heiferman JR;Shrivastav M;Vitello D;Blatner NR;Knab LM;Phillips JD;Cheon EC;Grippo PJ;Khazaie K;Munshi HG;Bentrem DJ
花生四烯酸代谢的产物白三烯和洋地黄素维持全身性和病变局部炎症。肿瘤相关性炎症也可能导致结肠癌的发病机制。炎症性肠病（IBD）患者患结肠癌的风险增加。5-脂氧合酶（5-LO）是产生白三烯的关键酶，其水平在结肠癌标本和结肠发育不良病变中升高。在这里，我们报告了一种特异性5-LO抑制剂齐留通可以通过有效地减少APCΔ468小鼠的肿瘤相关性和全身性炎症来预防息肉形成。在本研究中，我们通过饮食给予APCΔ468息肉病小鼠模型中的齐留通来抑制5-LO，并分析了体内5-LO抑制对肿瘤相关和全身炎症的影响。喂食齐留通的小鼠息肉较少，全身性炎症和息肉相关炎症明显减少。促炎性细胞因子和促炎性先天性和适应性免疫细胞在病变和全身都减少。作为肿瘤相关炎症的一部分，白三烯B4（LTB 4），5-LO活性的产物，在人类发育异常病变中局灶性增加。齐留通治疗的息肉病小鼠血清中的5-LO酶活性降低。这项研究表明，在息肉病小鼠模型中，饮食给予5-LO特异性抑制剂可降低息肉负担，并表明齐留通可能是结肠癌高风险患者的潜在化学预防剂。
Leukotrienes and prostaglandins, products of arachidonic acid metabolism, sustain both systemic and lesion-localized inflammation. Tumor-associated Inflammation can also contribute to the pathogenesis of colon cancer. Patients with inflammatory bowel disease (IBD) have increased risk of developing colon cancer. The levels of 5-lipoxygenase (5-LO), the key enzyme for leukotrienes production, are increased in colon cancer specimens and colonic dysplastic lesions. Here we report that Zileuton, a specific 5-LO inhibitor, can prevent polyp formation by efficiently reducing the tumor-associated and systemic inflammation in APCΔ468 mice. In the current study, we inhibited 5-LO by dietary administration of Zileuton in the APCΔ468 mouse model of polyposis and analyzed the effect of in vivo 5-LO inhibition on tumor-associated and systemic inflammation. Zileuton-fed mice developed fewer polyps and displayed marked reduction in systemic and polyp-associated inflammation. Pro-inflammatory cytokines and pro-inflammatory innate and adaptive immunity cells were reduced both in the lesions and systemically. As part of tumor-associated inflammation Leukotriene B4 (LTB4), product of 5-LO activity, is increased focally in human dysplastic lesions. The 5-LO enzymatic activity was reduced in the serum of Zileuton treated polyposis mice. This study demonstrates that dietary administration of 5-LO specific inhibitor in the polyposis mouse model decreases polyp burden, and suggests that Zileuton may be a potential chemo-preventive agent in patients that are high-risk of developing colon cancer.
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影响因子：
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