title: Statins induce apoptosis and inhibit proliferation in cholangiocarcinoma cells.
abstract: Given the poor prognosis for cholangiocarcinoma, new and effective treatments are urgently needed. HMG-CoA reductase inhibitors (statins) reportedly exert anticancer effects in a variety of diseases, but there have been no reports of these effects in cholangiocarcinoma. In this study, we investigated the utility of statins for cholangiocarcinoma treatment. Proliferation suppression by pitavastatin and atorvastatin was investigated in the human cholangiocarcinoma cell lines HuCCT1 and YSCCC while changes in the cell cycle and intracellular signals were examined by FACS and Western blotting, respectively. Additive proliferation suppression by statins and pre-existing anticancer drugs was also investigated. HuCCT1 and YSCCC cell proliferation was dramatically suppressed by incubation with statins for 72 h or longer. Cell cycle analysis revealed a reduction in the G2M fraction and an increase in the sub-G1 fraction in statin-treated cells, while Western blotting showed increased levels of cleaved caspase-3 and a reduction in p-ERK. Furthermore, statins in combination with gemcitabine, cisplatin and 5-FU showed additive proliferation suppression. In this study, treatment of human cholangiocarcinoma cells with statins induced apoptosis via suppression of the classical MAPK pathway. Together, these results suggest that statins may be a new cholangiocarcinoma treatment option that could potentially enhance the anticancer effect of pre-existing anticancer drugs.
authors.affiliation: Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biochemical Research, Graduate School of Biochemical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan. m-kamigaki@hiroshima-u.ac.jp
authors.forename: Michihiro
authors.initials: M
authors.lastname: Kamigaki
authors.forename: Tamito
authors.initials: T
authors.lastname: Sasaki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Serikawa
authors.forename: Motoki
authors.initials: M
authors.lastname: Inoue
authors.forename: Kenso
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itsuki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Minami
authors.forename: Masanobu
authors.initials: M
authors.lastname: Yukutake
authors.forename: Akihito
authors.initials: A
authors.lastname: Okazaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishigaki
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Ishii
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kosaka
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D011804:Quinolines; D000069059:Atorvastatin; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; C108475:pitavastatin