硼替佐米诱导肿瘤特异性的细胞死亡和抑制肝癌生长改善肝

StephenW

Journal of Gastroenterology
June 2013, Volume 48, Issue 6, pp 738-750
Bortezomib induces tumor-specific cell death and growth inhibition in hepatocellular carcinoma and improves liver fibrosis

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


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.

StephenW

人类肝细胞癌（HCC）是高度泛素化。泛素化是重要的肝癌generatation的。在体外和体内的抗肿瘤和抗纤维化作用的泛素 - 蛋白酶体系统抑制剂，硼替佐米，肝癌，肝硬化（LC）进行分析。
方法

硼替佐米的影响进行了分析在大鼠肝癌模型使用DEN和CDAA饮食（DEN / CDAA模型），它显示了严重的LC和代肝癌。 GST-P阳性灶和HCC的减少在体内进行了分析。分析细胞死亡细胞凋亡检测试剂盒。肝纤维化检查天狼星红染色和α-平滑肌肌动蛋白染色。体外研究涉及3个肝癌细胞株（HepG2细胞，HUH7和HLF）和原代大鼠和人类肝细胞。肝癌细胞株增殖率进行了分析，采用MTT法和流式细胞仪分析。采用LDH释放法为主要的人力和大鼠肝细胞的毒性硼替佐米检查。
结果

在大鼠肝癌模型中，硼替佐米阻止癌前病变的发展，在肝癌组织中肝癌，特别诱导的细胞死亡过程中的早期阶段。此外，硼替佐米抑制细胞增殖，诱导肿瘤特异性的细胞死亡减少cyclin D1和磷酸化Rb的表达在肝癌细胞株。此外，硼替佐米原代大鼠和人肝细胞没有表现出肝毒性，这表明它可能是一种肝癌特异性药物。硼替佐米也阻止肝星状细胞的活化和抑制肝纤维化DEN / CDAA模型的。
结论

硼替佐米似乎是一个理想的LC肝癌的靶向药物。