Free Radic Biol Med 2011 Dec;51 (12): 2259-71. [IF:5.707]
Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: A potential new treatment for hepatocellular carcinoma.
Gong K , Li W .
College of Life Sciences, Wuhan University, Wuhan 430072, People's Republic of China.
武汉大学生命科学学院
Abstract
Although shikonin, a naphthoquinone derivative, has showed anti-cancer activity, its precise molecular anti-tumor 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-κB 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-κB, but Akt or RIP1/NF-κB did not regulate ROS generation, suggesting that Akt and RIP1/NF-κB 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-κB pathways.
摘要：
紫草醌是萘醌的衍生物，虽然已有研究显示紫草醌具有抗肿瘤活性,但是其精确的抗肿瘤分子机制有待阐明。本研究通过体内和体外试验研究紫草醌对人肝细胞癌(HCC)的影响。结果表明, 紫草醌诱导Huh7 和 BEL7402细胞凋亡,但不会导致非肿瘤细胞死亡。 研究中检测到活性氧的产生,且活性氧清除剂能完全抑制紫草醌诱导的细胞凋亡,表明在诱导细胞凋亡中活性氧起重要作用。虽然紫草醌治疗后，氨基端激酶活性显著提高，但是氨基端激酶与细胞凋亡无关。然而紫草醌诱导的细胞凋亡中发现苏氨酸蛋白激酶（Akt）和RIP1/NF-κB活化抑制。Akt 或 RIP1的异位表达能部分消除紫草醌的影响，Akt和RIP1抑制剂在协同紫草醌治疗诱导细胞凋亡时起协同作用，ROS清除剂阻断了紫草醌诱导的Akt 和 RIP1/NF-κB的失活，但是Akt 或 RIP1/NF-κB不能调控ROS生成，即Akt和RIP1/NF-κB信号抑制ROS产生。另外，小鼠异种移植试验结果与体外研究结果一致。数据显示，紫草醌可能是治疗肝脏肿瘤的一种有前景的药物，他通过ROS/Akt以及 RIP1/NF-κB信号通路诱导人肝癌细胞凋亡。
