title: Bortezomib induces tumor-specific cell death and growth inhibition in hepatocellular carcinoma and improves liver fibrosis.
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.
authors.affiliation: Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi, Ube, Yamaguchi, 755-8505, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Saeki
authors.forename: Shuji
authors.initials: S
authors.lastname: Terai
authors.forename: Koichi
authors.initials: K
authors.lastname: Fujisawa
authors.forename: Taro
authors.initials: T
authors.lastname: Takami
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Hirose
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Murata
authors.forename: Takahiro
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Isao
authors.initials: I
authors.lastname: Sakaida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib