Reactive oxygen species is essential for cycloheximide to sensitize lexatumumab-induced apoptosis in hepatocellular carcinoma cells.
Reactive oxygen species is essential for cycloheximide to sensitize lexatumumab-induced apoptosis in hepatocellular carcinoma cells.
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DOI：
10.1371/journal.pone.0016966
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发表时间：
2011-02-10
期刊：
影响因子：
3.7
通讯作者：
Liu C
中科院分区：
文献类型：
--
作者：
Zhao X;Cao M;Liu JJ;Zhu H;Nelson DR;Liu C
本研究旨在探讨 lexatumumab (Lexa) 在肝细胞癌 (HCC) 细胞中诱导的细胞凋亡。我们评估了 HCC 细胞系和正常人肝细胞对 Lexa 的敏感性，并探讨了 HCC 细胞对放线菌酮 (CHX) 诱导的 Lexa 细胞凋亡的敏感性。我们的数据表明，CHX 使 HCC 细胞系对 Lexa 诱导的细胞凋亡敏感，而单独使用 CHX 或 Lexa 的治疗是无效的。 CHX 随后 Lexa 的序贯治疗显着诱导 HCC 细胞中 caspase 依赖性细胞凋亡，并协同增加细胞内活性氧 (ROS) 的速率。此外，当 N-乙酰基-L-半胱氨酸 (NAC) 阻断 ROS 产生时，HCC 细胞可以免受 Lexa 和 CHX 联合治疗诱导的细胞凋亡。 Lexa 和 CHX 联合处理诱导的 ROS 生成触发促凋亡蛋白 Bax 寡聚化、构象变化和易位至线粒体，导致细胞色素 c 的释放和随后的细胞死亡。此外，HSP90 参与介导 Lexa 和 CHX 联合治疗诱导的 ROS 增加和细胞凋亡。更重要的是，我们观察到 Lexa 和 CHX 的联合治疗不会引起正常人原代肝细胞的凋亡毒性。这些结果表明，Lexa 和 CHX 联合治疗值得研究，以开发 HCC 患者的疗法。
This study aims to investigate apoptosis induced by lexatumumab (Lexa) in hepatocellular carcinoma (HCC) cells. We assessed the sensitivity of HCC cell lines and normal human hepatocytes to Lexa and explored the sensitization of HCC cells to Lexa-induced apoptosis by cycloheximide (CHX). Our data indicated that CHX sensitized HCC cell lines to Lexa-induced apoptosis, whereas treatment using solely CHX or Lexa was ineffective. The sequential treatment of CHX followed by Lexa dramatically induced caspase-dependent apoptosis in HCC cells and had synergistically increased intracellular rates of reactive oxygen species (ROS). Additionally, when ROS production was blocked by N-acetyl-L-cysteine (NAC), HCC cells were protected against Lexa and CHX combination treatment-induced apoptosis. ROS generation induced by combination treatment of Lexa and CHX triggered pro-apoptotic protein Bax oligomerization, conformation change, and translocation to mitochondria, which resulted in the release of cytochrome c and subsequent cell death. Furthermore, HSP90 was involved in mediating Lexa and CHX combination treatment-induced ROS increase and apoptotic death. More importantly, we observed that combination treatment of Lexa and CHX did not cause apoptotic toxicity in normal human primary hepatocytes. These results suggest that Lexa and CHX combination treatment merits investigation for the development of therapies for patients with HCC.
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