iNOS-dependent DNA damage via NF-κB expression in hamsters infected with Opisthorchis viverrini and its suppression by the antihelminthic drug praziquantel
iNOS-dependent DNA damage via NF-κB expression in hamsters infected with Opisthorchis viverrini and its suppression by the antihelminthic drug praziquantel
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DOI：
10.1002/ijc.21893
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发表时间：
2006-09-01
影响因子：
6.4
通讯作者：
Kawanishi, Shosuke
中科院分区：
文献类型：
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作者：
Pinlaor, Somehai;Hiraku, Yusuke;Kawanishi, Shosuke
由猫尾后睾吸虫（OV）感染引发的炎症介导的DNA损伤是胆管癌（CCA）的主要危险因素。我们最近报道了硝化和氧化DNA损伤参与由OV重复感染引起的CCA发展[Pinlaor et al.，Carcinogenesis 2004; 25：1535-42]。因此，为了阐明抗蠕虫药物吡喹酮对胆管癌发生的预防作用，我们评估了这种药物对硝化和氧化DNA损伤的影响，包括8-硝基鸟嘌呤和8-氧代-7，8-二氢-2 '-脱氧鸟苷（8-oxodG）的形成，以及通过免疫组织化学在OV感染的仓鼠中诱导型一氧化氮合酶（iNOS）的表达。我们还检测了核因子-κ B（NF-κ B）的表达，NF-κ B在炎症相关癌症中起肿瘤促进作用。我们的研究结果表明，虽然1周的治疗吡喹酮没有完全杀死寄生虫在仓鼠的第14和30天，这种药物显着减少炎症细胞浸润。双重免疫荧光染色显示，药物治疗几乎完全减少了OV诱导的胆管上皮细胞中8-硝基鸟嘌呤和8-oxodG的形成。使用与HPLC偶联的电化学检测器的定量分析显示，经药物治疗，OV感染的仓鼠的肝脏中的8-oxodG水平显著降低（p < 0.05）。Western blotting和免疫组化结果显示，药物治疗可降低胆管上皮NF-κ B和iNOS的表达。药物治疗后，肝脏和血浆中硝酸盐和亚硝酸盐的量显着降低。结论吡喹酮通过抑制iNOS依赖的DNA损伤，不仅能清除体内寄生虫，还具有潜在的抗炎作用，从而对OV诱导的胆管癌具有预防作用。(c)2006 Wiley-Liss，Inc.
Inflammation-mediated DNA damage triggered by Opisthorchis viverrini (OV) infection is a major risk factor of cholangiocarcinoma (CCA). We have recently reported that nitrative and oxidative DNA damage participates in CCA development caused by repeated infection with OV [Pinlaor et al., Carcinogenesis 2004; 25:1535-42]. Therefore, to clarify the preventive effect of the anti-helminthic drug praziquantel against cholangiocarcinogenesis, we assessed the effect of this drug on nitrative and oxidative DNA damage, including the formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and the expression of inducible nitric oxide synthase (iNOS) by immunohistochemistry in OV-infected hamsters. We also examined the expression of nuclear factor-kappa B (NF-kappa B), which functions as a tumor promoter in inflammation-associated cancer. Our results showed that although 1-week treatment with praziquantel did not kill parasites completely in hamsters on days 14 and 30, this drug dramatically reduced inflammatory cell infiltration. Double immunofluorescence staining showed that drug treatment almost completely diminished OV-induced 8-nitroguanine and 8-oxodG formation in bile duct epithelial cells. Quantitative analysis using an electrochemical detector coupled to HPLC revealed that 8-oxodG level in the liver of OV-infected hamsters was significantly decreased by drug treatment (p < 0.05). Western blotting and immunohistochemistry revealed that the expression of NF-kappa B and iNOS in bile duct epithelium was reduced by drug treatment. The amount of nitrate plus nitrite in the liver and plasma was significantly decreased after drug treatment. It is concluded that praziquantel can exhibit a preventive effect against OV-induced cholangiocarcinoma by inhibiting iNOS-dependent DNA damage through not only elimination of parasites but also a potential anti inflammatory effect. (c) 2006 Wiley-Liss, Inc.