iNOS-dependent DNA damage via NF-κB expression in hamsters infected with Opisthorchis viverrini and its suppression by the antihelminthic drug praziquantel

Authors

  • Somchai Pinlaor,

    1. Department of Parasitology, Khon Kaen University, Khon Kaen, Thailand
    2. Department of Environmental and Molecular Medicine Mie University Graduate School of Medicine, Mie, Japan
    3. Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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  • Yusuke Hiraku,

    1. Department of Environmental and Molecular Medicine Mie University Graduate School of Medicine, Mie, Japan
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  • Puangrat Yongvanit,

    1. Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
    2. Department of Biochemistry, Khon Kaen University, Khon Kaen, Thailand
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  • Saeko Tada-Oikawa,

    1. Department of Environmental and Molecular Medicine Mie University Graduate School of Medicine, Mie, Japan
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  • Ning Ma,

    1. Department of Anatomy, Mie University Graduate School of Medicine, Mie, Japan
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  • Porntip Pinlaor,

    1. Department of Clinical Microbiology, Faculty of Associated Medical Science, Khon Kaen University, Khon Kaen, Thailand
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  • Paiboon Sithithaworn,

    1. Department of Parasitology, Khon Kaen University, Khon Kaen, Thailand
    2. Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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  • Banchob Sripa,

    1. Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
    2. Department of Pathology, Khon Kaen University, Khon Kaen, Thailand
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  • Mariko Murata,

    1. Department of Environmental and Molecular Medicine Mie University Graduate School of Medicine, Mie, Japan
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  • Shinji Oikawa,

    1. Department of Environmental and Molecular Medicine Mie University Graduate School of Medicine, Mie, Japan
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  • Shosuke Kawanishi

    Corresponding author
    1. Department of Environmental and Molecular Medicine Mie University Graduate School of Medicine, Mie, Japan
    • Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, 2-174, Edobashi, Tsu, Mie 514-8507, Japan
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    • Fax: +81 (59) 231-5011


Abstract

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 antihelminthic 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-κB (NF-κB), 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-κB 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 antiinflammatory effect. © 2006 Wiley-Liss, Inc.

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