Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan.
Oncol Rep. 2010 Jul;24(1):31-6. doi: 10.3892/or_00000825.
Inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 are major inflammatory mediators. Nitric oxide (NO) produced by iNOS has been shown to have an important role in carcinogenesis. Recent studies have suggested that COX-2 expression also contributes to carcinogenesis, as well as tumor growth, invasion, and metastasis. COX-2 inhibitors such as celecoxib are widely recognized to have antitumor activity, but can cause adverse effects. We investigated possible relations between COX-2 and NO with the use of a human epidermoid carcinoma cell line, designated KB, in which overexpression of COX-2 protein was induced by gene transfer. We also assessed the possibility of using NOS inhibitor as an antitumor drug. We isolated a COX-2 transfected clone (KB/COX-2) and used a neomycin-transfected clone (KB/neo) as control. NG-nitro-L-arginine-methyl ester (L-NAME) was used as a NOS inhibitor, dihydrochloride (1400W) as an iNOS inhibitor, and celecoxib as a selective COX-2 inhibitor. All agents inhibited the cell growth of both clones to similar extents in a dose-dependent manner. Prostaglandin E2 (PGE2) production and COX-2 expression in KB/COX-2 were inhibited not only by celecoxib, but also by L-NAME and 1400W. The decreases in PGE2 production and COX-2 expression were most prominent with celecoxib and L-NAME. In vivo, L-NAME and celecoxib significantly inhibited the proliferation of KB/COX-2-xenografted tumors. Tumor weight was reduced by L-NAME (60.6% decrease), 1400W (38.0% decrease), and celecoxib (74.5% decrease) as compared with the control after 21 days of treatment. Immunohistochemically, xenografted tumors expressed COX-2, iNOS, and eNOS. Such expression was suppressed by treatment with L-NAME and celecoxib. These results suggest that L-NAME and celecoxib significantly inhibit the proliferation of murine squamous cell carcinoma in vivo. L-NAME as well as celecoxib might thus be useful for the design and development of new antitumor drugs.
诱导型一氧化氮合酶 (iNOS) 和环氧化酶 (COX)-2 是主要的炎症介质。已经表明，iNOS 产生的一氧化氮 (NO) 在致癌作用中具有重要作用。最近的研究表明，COX-2 的表达也有助于致癌作用以及肿瘤的生长、侵袭和转移。广泛认为 COX-2 抑制剂如塞来昔布具有抗肿瘤活性，但可能会引起不良反应。我们使用基因转移诱导过表达 COX-2 蛋白的人表皮癌细胞系 KB 研究了 COX-2 和 NO 之间的可能关系。我们还评估了使用 NOS 抑制剂作为抗肿瘤药物的可能性。我们分离了 COX-2 转染的克隆 (KB/COX-2)，并使用新霉素转染的克隆 (KB/neo) 作为对照。NG-硝基-L-精氨酸甲酯 (L-NAME) 用作 NOS 抑制剂，二盐酸 (1400W) 用作 iNOS 抑制剂，塞来昔布用作选择性 COX-2 抑制剂。所有药物均以剂量依赖性方式相似程度地抑制了两个克隆的细胞生长。PG E2 (PGE2) 的产生和 COX-2 在 KB/COX-2 中的表达不仅被塞来昔布抑制，而且被 L-NAME 和 1400W 抑制。PGE2 产生和 COX-2 表达的减少以塞来昔布和 L-NAME 最为明显。在体内，L-NAME 和塞来昔布显著抑制 KB/COX-2 异种移植肿瘤的增殖。与对照组相比，L-NAME (减少 60.6%)、1400W (减少 38.0%) 和塞来昔布 (减少 74.5%) 处理 21 天后，肿瘤重量降低。免疫组织化学染色显示，异种移植肿瘤表达 COX-2、iNOS 和 eNOS。L-NAME 和塞来昔布处理可抑制其表达。这些结果表明，L-NAME 和塞来昔布可显著抑制体内小鼠鳞状细胞癌的增殖。L-NAME 和塞来昔布可能有助于新抗肿瘤药物的设计和开发。
