Chemoprevention of Colon Cancer by iNOS-Selective Inhibitors.
Chemoprevention of Colon Cancer by iNOS-Selective Inhibitors.
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DOI：
10.1615/forumimmundisther.2012006186
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Rao CV
中科院分区：
文献类型：
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作者：
Janakiram NB;Rao CV
一氧化氮（NO）是一种短暂的多效性调节剂，是许多病理生理功能所必需的，包括巨噬细胞介导的免疫和癌症。它是一种高活性的自由基，由L-精氨酸通过不同亚型的一氧化氮合酶（NOS）产生。在慢性炎性病症期间诱导型NOS（iNOS）的持续诱导导致NO的反应性中间体的形成，所述反应性中间体是致突变的并且引起DNA损伤或DNA修复的损害，改变细胞信号传导，并且促进细胞的促炎和血管生成性质，从而促成致癌作用。除了其在炎症中的明确作用外，在结直肠肿瘤和其他癌症中观察到iNOS表达增加。参与结肠肿瘤发生的NO相关信号通路似乎通过刺激促炎细胞因子和通过肿瘤中重要抗凋亡分子的翻译后蛋白修饰而进展。NO可通过促进侵袭性、血管生成和迁移活动刺激和增强肿瘤细胞增殖。相反，研究还表明，高水平的NO可能通过诱导肿瘤细胞死亡来保护肿瘤生长。然而，许多体外研究，特别是实验动物数据支持的概念，NO和其反应性代谢产物过氧亚硝酸盐刺激环氧合酶-2活性，导致生成的三尖杉酯碱，增强肿瘤生长。这些洋地黄素进一步增强肿瘤促进和肿瘤细胞的侵袭特性。因此，选择性iNOS抑制剂和联合策略，以抑制iNOS和环氧合酶-2可能有预防作用，在结肠癌。
Nitric oxide (NO) is a short-lived pleiotropic regulator and is required for numerous pathophysiological functions, including macrophage-mediated immunity and cancer. It is a highly reactive free radical produced from l-arginine by different isoforms of NO synthases (NOSs). Sustained induction of inducible NOS (iNOS) during chronic inflammatory conditions leads to the formation of reactive intermediates of NO, which are mutagenic and cause DNA damage or impairment of DNA repair, alter cell signaling, and promote proinflammatory and angiogenic properties of the cell, thus contributing to carcinogenesis. Besides its well-established role in inflammation, increased expression of iNOS has been observed in colorectal tumors and other cancers. NO-related signaling pathways involved in colon tumorigenesis seem to progress through stimulation of proinflammatory cytokines and via posttranslational protein modifications of important antiapoptotic molecules in the tumors. NO can stimulate and enhance tumor cell proliferation by promoting invasive, angiogenic, and migratory activities. In contrast, studies also suggest that high levels of NO may be protective against tumor growth by inducing tumor cell death. However, a number of in vitro studies and particularly experimental animal data support the notion that NO and its reactive metabolite peroxynitrite stimulate cyclooxygenase-2 activity, leading to generation of prostaglandins that enhance tumor growth. These prostaglandins further augment tumor promotion and invasive properties of tumor cells. Hence, selective inhibitors of iNOS and combination strategies to inhibit both iNOS and cyclooxygenase-2 may have a preventive role in colon cancer.