Melatonin inhibits cholangiocarcinoma and reduces liver injury in Opisthorchis viverrini-infected and N-nitrosodimethylamine-treated hamsters

Authors

  • Umawadee Laothong,

    1. Department of Parasitology, Faculty of Medicine, 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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  • Porntip Pinlaor,

    1. Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
    2. Centre for Research and Development in Medical Diagnostic Laboratory, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
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  • Patcharee Boonsiri,

    1. Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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  • Chawalit Pairojkul,

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

    1. Division of Pharmaceutical Technology, and Melatonin Research group Khon Kaen University, Khon Kaen, Thailand
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  • Nutjaree Pratheepawanit Johns,

    1. Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, and Melatonin Research group, Khon Kaen University, Khon Kaen, Thailand
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  • Lakhanawan Charoensuk,

    1. Department of Parasitology, Faculty of Medicine, 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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  • Kitti Intuyod,

    1. Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
    2. Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
    3. Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, Thailand
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  • Somchai Pinlaor

    Corresponding author
    1. Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
    • Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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Address reprint requests to Somchai Pinlaor, Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.

E-mail: psomec@kku.ac.th

Abstract

The human liver fluke Opisthorchis viverrini infection and N-nitrosodimethylamine (NDMA) administration induce cholangiocarcinoma (CCA) and liver injury in hamsters. Melatonin protects against liver injury and reduces the alteration of mitochondrial structure, mitochondrial membrane potential, and mitochondrial pro- and anti-apoptotic pathways in various cancer types. To investigate the chemopreventive effect of melatonin on CCA genesis and liver injury, hamsters were treated with a combination of O. viverrini infection and NDMA concurrently administered with melatonin (10 mg/kg and 50 mg/kg) for 120 days. Melatonin treatment at 50 mg/kg caused a significant reduction in liver/body weight ratios and decreased tumor volumes leading to an increase in the survival of animals. In the tumorous tissues, the high-dose melatonin reduced DNA fragmentation and mitochondrial apoptosis by inducing anti-apoptotic protein (Bcl-2) in the mitochondrial fraction and down-regulating cytochrome c, pro-apoptotic protein (Bax), and caspase-3 in tumor cytosol. Moreover, a high-dose melatonin treatment significantly increased mitochondrial antioxidant enzymes and prevented mitochondrial ultrastructure changes in the tumor. Overall, melatonin has potent chemopreventive effects in inhibiting CCA genesis and also reduces liver injury in hamster CCA, which, in part, might involve in the suppression of CCA by reducing tumor mitochondria alteration.

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