caa a22 4500 445887893 CHVBK 20180317145605.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s00535-011-0380-3 doi (NATIONALLICENCE)springer-10.1007/s00535-011-0380-3 Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells [Elektronische Daten] [Hiroaki Sugiyama, Kenichiro Onuki, Kazunori Ishige, Nobue Baba, Tetsuya Ueda, Sachiko Matsuda, Kaoru Takeuchi, Masafumi Onodera, Yasuni Nakanuma, Masayuki Yamato, Masakazu Yamamoto, Ichinosuke Hyodo, Junichi Shoda] Background: Intrahepatic cholangiocarcinoma (ICC) is rising in clinical importance due to the increasing incidence worldwide, poor prognosis, and suboptimal response to therapies. New effective therapeutic approaches are needed for improvement of treatment outcome. A recent study showed that sorafenib, a multikinase inhibitor that acts predominantly through inhibition of Raf kinase and vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, exhibited potent antitumor activity in a preclinical model of cholangiocarcinoma cells. Method: We tested the in vitro and in vivo antitumor activity of sorafenib against human ICC cell lines. Results: Treatment of ICC cells with sorafenib resulted in inhibition of proliferation and induction of apoptosis in the cell lines. In the cells treated with sorafenib, phosphorylation of mitogen-activated protein kinase kinase (MEK) and mitogen-activated protein kinase (MAPK) and also interleukin-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) were inhibited in a dose-dependent manner. Down-regulation of the anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) paralleled the reduced phosphorylation of STAT3. However, sorafenib induced no significant change in the cell cycle distribution and the expression levels of cyclin D1 and p27Kip1 in the cells. For the in vivo antitumor activity, oral administration of sorafenib significantly inhibited the growth of subcutaneous tumors established in immunodeficient mice at doses of 10, 30, and 100mg/kg. Moreover, administration of sorafenib (30mg/kg) to animals with peritoneally disseminated ICC resulted in significantly prolonged survival compared with that of untreated animals (76 vs. 43days in treated and vehicle-treated mice, respectively). Conclusion: These results indicate that sorafenib is a potent agent that may provide a new therapeutic option for human ICC. Springer, 2011 Cholangiocarcinoma nationallicence Molecular targeting therapy nationallicence Multi-tyrosine kinase inhibitor nationallicence Antitumor activity nationallicence Preclinical study nationallicence Ab : Antibody nationallicence AKT/PKB : Protein kinase B nationallicence CC : Cholangiocarcinoma nationallicence IH : Intrahepatic nationallicence IL-6 : Interleukin-6 nationallicence JAK : Janus kinase nationallicence MAPK : Mitogen-activated protein kinase nationallicence Mcl-1 : Myeloid cell leukemia-1 nationallicence MEK : Mitogen-activated protein kinase kinase nationallicence STAT : Signal transducer and activator of transcription nationallicence Sugiyama Hiroaki Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut Onuki Kenichiro Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan aut Ishige Kazunori Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut Baba Nobue Pharmacodynamics Group, Drug Development Service Division, Medi-Chem Business Segment, Itabashi-ku, Tokyo, Japan aut Ueda Tetsuya Pharmacodynamics Group, Drug Development Service Division, Medi-Chem Business Segment, Itabashi-ku, Tokyo, Japan aut Matsuda Sachiko Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan aut Takeuchi Kaoru Department of Infection Biology, Institute of Basic Medical Science, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut Onodera Masafumi Department of Genetics, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan aut Nakanuma Yasuni Department of Human Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan aut Yamato Masayuki Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan aut Yamamoto Masakazu Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan aut Hyodo Ichinosuke Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut Shoda Junichi Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut Journal of Gastroenterology Springer Japan 46/6(2011-06-01), 779-789 0944-1174 46:6<779 2011 46 535 https://doi.org/10.1007/s00535-011-0380-3 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s00535-011-0380-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sugiyama Hiroaki Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut NATIONALLICENCE 700 1- Onuki Kenichiro Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Ishige Kazunori Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut NATIONALLICENCE 700 1- Baba Nobue Pharmacodynamics Group, Drug Development Service Division, Medi-Chem Business Segment, Itabashi-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Ueda Tetsuya Pharmacodynamics Group, Drug Development Service Division, Medi-Chem Business Segment, Itabashi-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Matsuda Sachiko Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Takeuchi Kaoru Department of Infection Biology, Institute of Basic Medical Science, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut NATIONALLICENCE 700 1- Onodera Masafumi Department of Genetics, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Nakanuma Yasuni Department of Human Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan aut NATIONALLICENCE 700 1- Yamato Masayuki Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Yamamoto Masakazu Department of Surgery, Institute of Gastroenterology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan aut NATIONALLICENCE 700 1- Hyodo Ichinosuke Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut NATIONALLICENCE 700 1- Shoda Junichi Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan aut NATIONALLICENCE 773 0- Journal of Gastroenterology Springer Japan 46/6(2011-06-01), 779-789 0944-1174 46:6<779 2011 46 535 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer