title: Melatonin induces apoptosis in cholangiocarcinoma cell lines by activating the reactive oxygen species-mediated mitochondrial pathway.
abstract: We previously demonstrated that melatonin could be used as a chemopreventive agent for inhibiting cholangiocarcinoma (CCA) development in a hamster model. However, the cytotoxic activity of melatonin in cancer remains unclear. In the present study, we investigated the effect of melatonin on CCA cell lines. Human CCA cell lines (KKU-M055 and KKU-M214) were treated with melatonin at concentrations of 0.5, 1 and 2 mM for 48 h. Melatonin treatment exerted a cytotoxic effect on CCA cells by inhibiting CCA cell viability in a concentration-dependent manner. Treatment with melatonin, especially at 2 mM, increased intracellular reactive oxygen species (ROS) production and in turn led to increased oxidative DNA damage and 8-oxodG formation. Moreover, melatonin treatment enhanced the production of cytochrome c leading to apoptosis in a concentration-dependent manner, as indicated by increased expression of apoptosis-related proteins caspase-3 and caspase-7. In conclusion, melatonin acts as a pro-oxidant by activating ROS-dependent DNA damage and thus leading to the apoptosis of CCA cells.
authors.affiliation: Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Umawadee
authors.initials: U
authors.lastname: Laothong
authors.affiliation: Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 514‑8507, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.affiliation: Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 514‑8507, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Oikawa
authors.affiliation: Liver Fluke and Cholangiocarcinoma Research Center, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Kitti
authors.initials: K
authors.lastname: Intuyod
authors.affiliation: Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 514‑8507, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.affiliation: Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Somchai
authors.initials: S
authors.lastname: Pinlaor
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D045744:Cell Line, Tumor; D002470:Cell Survival; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D006801:Humans; D008550:Melatonin / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D008550:Melatonin