Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: A potential new treatment for hepatocellular carcinoma
Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: A potential new treatment for hepatocellular carcinoma
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DOI：
10.1016/j.freeradbiomed.2011.09.018
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发表时间：
2011-12-15
影响因子：
7.4
通讯作者：
Li, Wenhua
中科院分区：
文献类型：
--
作者：
Gong, Ke;Li, Wenhua
紫草素是一种萘醌类化合物，具有抗癌活性，但其确切的分子抗肿瘤机制尚不清楚。在本研究中，我们研究了紫草素在体内外对人肝细胞癌的作用。结果表明，紫草素可诱导HuH7和BEL7402细胞的凋亡，但不能诱导非致瘤细胞的凋亡。检测到ROS的产生，ROS清除剂完全抑制紫草素诱导的细胞凋亡，表明ROS起着至关重要的作用。尽管紫草素治疗后JNK活性显著升高，但JNK与细胞凋亡无关。然而，Akt和RIP1/NF-kappaB活性下调被发现参与了紫草素诱导的细胞凋亡。异位表达Akt或RIP1可部分阻断紫草素的作用，Akt抑制剂和RIP1抑制剂联合紫草素处理可协同诱导细胞凋亡。ROS清除剂阻断紫草素诱导的Akt和RIP1/NF-kappa B的失活，但Akt或RIP1/NF-kappa B不调节ROS的产生，提示ALA和RIP1/NF-kappa B信号位于ROS产生的下游。此外，小鼠异种移植实验结果与体外实验结果一致。综上所述，我们的数据表明紫草素通过ROS/Akt和RIP1/NF-kappa B途径诱导肝癌细胞凋亡，可能是一种很有前途的治疗肝癌的药物。(C)2011 Elsevier Inc.保留所有权利。
Although shikonin, a naphthoquinone derivative, has showed anti-cancer activity, its precise molecular antitumor mechanism remains to be elucidated. In this study, we investigated the effects of shikonin on human hepatocellular carcinoma (HCC) in vitro and in vivo. Our results showed that shikonin induced apoptosis of Huh7 and BEL7402 but not nontumorigenic cells. ROS generation was detected, and ROS scavengers completely inhibited shikonin-induced apoptosis, indicating that ROS play an essential role. Although the JNK activity was significantly elevated after shikonin treatment, JNK was not linked to apoptosis. However, downregulation of Akt and RIP1/NF-kappa B activity was found to be involved in shikonin-induced apoptosis. Ectopic expression of Akt or RIP1 partly abrogated the effects of shikonin, and Akt inhibitor and RIP1 inhibitor synergistically induced apoptosis in conjunction with shikonin treatment. ROS scavengers blocked shikonin-induced inactivation of Akt and RIP1/NF-kappa B, but Akt or RIP1/NF-kappa B did not regulate ROS generation, suggesting that Ala and RIP1/NF-kappa B signals are downstream of ROS generation. In addition, the results of xenograft experiments in mice were consistent with in vitro studies. Taken together, our data show that shikonin, which may be a promising agent in the treatment of liver cancer, induced apoptosis in HCC cells through the ROS/Akt and RIP1/NF-kappa B pathways. (C) 2011 Elsevier Inc. All rights reserved.