Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma
Inhibition of autophagy enhances anticancer effects of bevacizumab in hepatocarcinoma
复制标题
抑制自噬增强贝伐珠单抗对肝癌的抗癌作用
DOI：
10.1007/s00109-012-0966-0
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发表时间：
2013-04-01
影响因子：
4.7
通讯作者：
Wei, Li-xin
中科院分区：
文献类型：
--
作者：
Guo, Xian-ling;Li, Ding;Wei, Li-xin
血管生成抑制剂长期以来一直被认为是理想的抗癌药物。然而，研究发现，许多肿瘤可能对抗血管生成抑制剂产生耐药性。抗血管生成治疗会导致代谢应激。自噬是肿瘤细胞在代谢应激状态下的一种重要的生存机制，但目前尚不清楚自噬是否会导致抗血管生成抵抗。在这项研究中，我们报道了贝伐单抗治疗减少了肝细胞癌移植瘤中新生血管的生长和抑制了细胞的生长。贝伐单抗治疗还上调了自噬相关基因(Beclin1和Lc3)的表达，并增加了自噬小体的形成。我们的体外研究表明，在营养缺乏或缺氧时，自噬抑制显著增加了肝癌细胞的凋亡。此外，自噬抑制因子与贝伐单抗联合应用明显抑制了肝癌移植瘤的生长，促进了肿瘤细胞的凋亡，抑制了肿瘤细胞的增殖。此外，自噬抑制导致体外暴露于营养物质饥饿或缺氧的肝癌细胞中活性氧物种(ROS)的产生增加，并增加体内DNA氧化损伤。抗氧化剂可减少自噬抑制后的营养饥饿或低氧诱导的肝癌细胞死亡。我们的结果表明，自噬调节ROS的产生，并有助于代谢应激下的细胞存活。因此，抑制自噬可能是提高抗血管生成药物治疗肝癌疗效的一种新途径。
Angiogenesis inhibitors have long been considered desirable anticancer agents. However, it was found that many tumors could develop resistance to antiangiogenesis inhibitors. Antiangiogenic therapy results in metabolic stress. Autophagy is an important survival mechanism in cancer cells under metabolic stress; however, it remains unknown if autophagy contributes to antiangiogenesis resistance. In this study, we reported that bevacizumab treatment reduced the development of new blood vessels and inhibited cell growth in xenografts of hepatocellular carcinoma (HCC) tumors. Bevacizumab treatment also upregulated expression of the autophagy-related genes (Beclin1 and LC3) and increased autophagosome formation. Our in vitro studies demonstrated that autophagy inhibition significantly increased apoptosis of HCC cells during nutrient starvation or hypoxia. In addition, the combined treatment of an autophagy inhibitor and bevacizumab markedly inhibited the tumor growth of HCC xenografts, led to enhanced apoptosis, and impaired the proliferation of tumor cells compared with treatment with either drug alone. Furthermore, autophagy inhibition led to enhanced reactive oxygen species (ROS) generation in HCC cells exposed to nutrient starvation or hypoxia in vitro and increased DNA oxidative damage in vivo. Antioxidants reduced nutrient starvation or the hypoxia-induced cell death of HCC cells after autophagy inhibition. Our results suggest that autophagy modulates ROS generation and contributes to cell survival under metabolic stress. Therefore, autophagy inhibition may be a novel way of increasing the efficicacy of antiangiogenic agents in the treatment of HCC.