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Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

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 100 mg/kg. Moreover, administration of sorafenib (30 mg/kg) to animals with peritoneally disseminated ICC resulted in significantly prolonged survival compared with that of untreated animals (76 vs. 43 days 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.

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Abbreviations

Ab:

Antibody

AKT/PKB:

Protein kinase B

CC:

Cholangiocarcinoma

IH:

Intrahepatic

IL-6:

Interleukin-6

JAK:

Janus kinase

MAPK:

Mitogen-activated protein kinase

Mcl-1:

Myeloid cell leukemia-1

MEK:

Mitogen-activated protein kinase kinase

STAT:

Signal transducer and activator of transcription

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Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (20390339, 22390379, 22591530).

Conflict of interest

All authors declare that they have no conflict of interests or financial interests.

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan

    Hiroaki Sugiyama, Kazunori Ishige, Ichinosuke Hyodo & Junichi Shoda

  2. Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

    Kenichiro Onuki & Masakazu Yamamoto

  3. Pharmacodynamics Group, Drug Development Service Division, Medi-Chem Business Segment, Itabashi-ku, Tokyo, Japan

    Nobue Baba & Tetsuya Ueda

  4. Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan

    Sachiko Matsuda

  5. Department of Infection Biology, Institute of Basic Medical Science, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan

    Kaoru Takeuchi

  6. Department of Genetics, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan

    Masafumi Onodera

  7. Department of Human Pathology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan

    Yasuni Nakanuma

  8. Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan

    Masayuki Yamato

  9. Field of Basic Sports Medicine, Sports Medicine, University of Tsukuba Graduate School of Comprehensive Human Sciences, Tsukuba, Ibaraki, Japan

    Junichi Shoda

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  1. Hiroaki Sugiyama
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  2. Kenichiro Onuki
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  3. Kazunori Ishige
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  6. Sachiko Matsuda
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  8. Masafumi Onodera
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  9. Yasuni Nakanuma
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  10. Masayuki Yamato
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  11. Masakazu Yamamoto
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  12. Ichinosuke Hyodo
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  13. Junichi Shoda
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Corresponding author

Correspondence to Junichi Shoda.

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Sugiyama, H., Onuki, K., Ishige, K. et al. Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells. J Gastroenterol 46, 779–789 (2011). https://doi.org/10.1007/s00535-011-0380-3

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  • DOI: https://doi.org/10.1007/s00535-011-0380-3

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