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Bortezomib induces tumor-specific cell death and growth inhibition in hepatocellular carcinoma and improves liver fibrosis

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

Background

Human hepatocellular carcinoma (HCC) is highly ubiquitinated. The ubiquitination is important to the generatation of HCC. The antitumor and antifibrosis effects of an ubiquitin–proteasome system inhibitor, bortezomib, on HCC with liver cirrhosis (LC) were analyzed in vitro and in vivo.

Methods

The effect of bortezomib was analyzed in the rat hepatocarcinogenesis model using a DEN and CDAA diet (DEN/CDAA model), which shows severe LC and generation of HCC. The decrease of GST-P-positive foci and HCC were analyzed in vivo. Cell death was analyzed by cell death detection kit. Liver fibrosis was checked by sirius-red staining and α-smooth muscle actin staining. The in vitro study involved 3 HCC cell lines (HepG2, HuH7, and HLF) and primary rat and human hepatocytes. The proliferation rate of the HCC cell line was analyzed using the MTT assay and FACS analysis. The toxicity of bortezomib was checked using the LDH release assay for primary human and rat hepatocytes.

Results

In the rat hepatocarcinogenesis model, bortezomib prevented the development of preneoplastic lesions during the early stages of hepatocarcinogenesis and specifically induced cell death in HCC. Furthermore, bortezomib inhibited cell proliferation and induced tumor-specific cell death in HCC cell lines with decrease of cyclin D1 and phospho-Rb expression. Further, bortezomib showed no hepatotoxicity of primary rat and human hepatocytes, suggesting that it might be an HCC-specific drug. Bortezomib also prevented the activation of hepatic stellate cells and inhibited the liver fibrosis of the DEN/CDAA model.

Conclusions

Bortezomib appears to be an ideal target drug for HCC with LC.

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Acknowledgments

This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (21659189 and 22390150), the Japan Science and Technology Agency, and the Ministry of Health, Labour and Welfare.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi, 755-8505, Japan

    Issei Saeki, Shuji Terai, Koichi Fujisawa, Taro Takami, Naoki Yamamoto, Toshihiko Matsumoto, Yoshikazu Hirose, Yasuhiko Murata, Takahiro Yamasaki & Isao Sakaida

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  1. Issei Saeki
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  2. Shuji Terai
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  3. Koichi Fujisawa
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  4. Taro Takami
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  5. Naoki Yamamoto
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  6. Toshihiko Matsumoto
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  7. Yoshikazu Hirose
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  8. Yasuhiko Murata
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  9. Takahiro Yamasaki
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  10. Isao Sakaida
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Correspondence to Shuji Terai.

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Saeki, I., Terai, S., Fujisawa, K. et al. Bortezomib induces tumor-specific cell death and growth inhibition in hepatocellular carcinoma and improves liver fibrosis. J Gastroenterol 48, 738–750 (2013). https://doi.org/10.1007/s00535-012-0675-z

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  • DOI: https://doi.org/10.1007/s00535-012-0675-z

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