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.

译文

背景:人类肝细胞癌(HCC)高度泛素化。泛素化对于肝癌的产生很重要。在体外和体内分析了泛素-蛋白酶体系统抑制剂硼替佐米对肝硬化肝细胞癌的抗肿瘤和抗纤维化作用。
方法:使用DEN和CDAA饮食(DEN / CDAA模型)分析了硼替佐米在大鼠肝癌模型中的作用,该模型显示出严重的LC和肝癌的产生。体内分析了GST-P阳性灶和HCC的减少。通过细胞死亡检测试剂盒分析细胞死亡。肝纤维化通过天青红色染色和α-平滑肌肌动蛋白染色检查。体外研究涉及3种HCC细胞系(HepG2,HuH7和HLF)以及原代大鼠和人类肝细胞。使用MTT测定和FACS分析来分析HCC细胞系的增殖速率。硼替佐米的毒性使用LDH释放测定法对原代人和大鼠肝细胞进行了检查。
结果:在大鼠肝癌发生模型中,硼替佐米预防了肝癌发生早期肿瘤前病变的发展,并特异性地诱导了肝癌细胞的死亡。此外,硼替佐米可抑制HCC细胞株的细胞增殖并诱导肿瘤特异性细胞死亡,并降低细胞周期蛋白D1和磷酸化Rb的表达。此外,硼替佐米未显示对原代大鼠和人肝细胞有肝毒性,表明它可能是HCC特异性药物。硼替佐米还阻止了肝星状细胞的活化,并抑制了DEN / CDAA模型的肝纤维化。
结论:硼替佐米似乎是LC伴肝癌的理想靶标药物。

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