Department of Medicine III, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Cell Death Dis. 2014 Jan 30;5(1):e1030. doi: 10.1038/cddis.2013.557.
The multi-kinase inhibitor Sorafenib increases the survival of patients with advanced hepatocellular carcinoma (HCC). Current data suggest that Sorafenib inhibits cellular proliferation and angiogenesis and promotes apoptosis. However, the underlying pro-apoptotic molecular mechanisms are incompletely understood. Here we compared the pro-apoptotic and anti-proliferative properties of Sorafenib in murine hepatoma cells and syngeneic healthy hepatocytes in vitro and in animal models of HCC and liver regeneration in vivo. In vitro, we demonstrate that cell cycle activity and expression of anti-apoptotic Bcl-2 like proteins are similarly downregulated by Sorafenib in Hepa1-6 hepatoma cells and in syngeneic primary hepatocytes. However, Sorafenib-mediated activation of caspase-3 and induction of apoptosis were exclusively found in hepatoma cells, but not in matching primary hepatocytes. We validated these findings in vivo by applying an isograft HCC transplantation model and partial hepatectomy (PH) in C57BL/6 mice. Sorafenib treatment activated caspase-3 and thus apoptosis selectively in small tumor foci that originated from implanted Hepa1-6 cells but not in surrounding healthy hepatocytes. Similarly, Sorafenib did not induce apoptosis after PH. However, Sorafenib treatment transiently inhibited cell cycle progression and resulted in mitotic catastrophe and enhanced non-apoptotic liver injury during regeneration. Importantly, Sorafenib-mediated apoptosis in hepatoma cells was associated with the expression of p53-upregulated-modulator-of-apoptosis (PUMA). In contrast, regenerating livers after PH revealed downregulation of PUMA and were completely protected from Sorafenib-mediated apoptosis. We conclude that Sorafenib induces apoptosis selectively in hepatoma cells but not in healthy hepatocytes and can additionally increase non-apoptotic hepatocyte injury in the regenerating liver.
多激酶抑制剂索拉非尼可提高晚期肝细胞癌（HCC）患者的生存率。目前的数据表明，索拉非尼可抑制细胞增殖和血管生成，促进细胞凋亡。然而，其潜在的促凋亡分子机制尚不完全清楚。在此，我们比较了索拉非尼在体外的肝癌细胞和同源正常肝细胞中的促凋亡和抗增殖特性，以及体内 HCC 和肝再生动物模型中的作用。体外，我们证明索拉非尼可下调 Hepa1-6 肝癌细胞和同源原代肝细胞的细胞周期活性和抗凋亡 Bcl-2 样蛋白的表达。然而，只有在肝癌细胞中观察到索拉非尼介导的 caspase-3 激活和细胞凋亡诱导，而在匹配的原代肝细胞中则没有。我们在体内通过应用 C57BL/6 小鼠的同种异体 HCC 移植模型和部分肝切除术（PH）验证了这些发现。索拉非尼治疗可选择性地激活 caspase-3 并诱导源自植入 Hepa1-6 细胞的小肿瘤灶中的凋亡，但不诱导周围正常肝细胞中的凋亡。同样，PH 后索拉非尼也不会诱导细胞凋亡。然而，索拉非尼治疗可短暂抑制细胞周期进程，并导致有丝分裂灾难和再生过程中增强非凋亡性肝损伤。重要的是，索拉非尼在肝癌细胞中的凋亡与 p53 上调凋亡调节剂（PUMA）的表达有关。相比之下，PH 后再生的肝脏会下调 PUMA，并完全免受索拉非尼诱导的凋亡。我们的结论是，索拉非尼可选择性地诱导肝癌细胞凋亡，而不会诱导正常肝细胞凋亡，并且在再生的肝脏中还会增加非凋亡性肝细胞损伤。
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