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首页> 外文期刊>Biochemical Pharmacology >Dihydroartemisinin exhibits antitumor activity toward hepatocellular carcinoma in vitro and in vivo
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Dihydroartemisinin exhibits antitumor activity toward hepatocellular carcinoma in vitro and in vivo

机译：双氢青蒿素在体外和体内均对肝细胞癌具有抗肿瘤活性

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摘要

Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin isolated from the traditional Chinese herb Artemisia annua L., has been shown to exhibit inhibitory effects on human cancer cells. However, its antitumor ability toward hepatocellular carcinoma (HCC) has not been studied. In this study, we demonstrated that DHA significantly inhibited HCC cell growth in vitro and in vivo via inducing G2/M cell cycle arrest and apoptosis. The induction of p21 and the inhibition of cyclin B and CDC25C contributed to DHA-induced G2/M arrest. DHA-induced apoptosis was associated with mitochondrial membrane depolarization, release of cytochrome c, activation of caspases, and DNA fragmentation. Activation of caspase 9 and caspase 3, but not caspase 8, was detected in DHA-treated cells. Attenuation of apoptosis in cells pretreated with Z-VAD-FMK suggested the involvement of caspase cascade. Furthermore, p53 facilitated apoptosis caused by DHA. Bcl-2 family proteins were also responsible for DHA-induced apoptosis. DHA exposure decreased Mcl-1 expression but increased the levels of Noxa and active Bak. Bak was released from the Mcl-1/Bak complex due to the decline of Mcl-1. Further study revealed that Mcl-1 was rapidly degraded in DHA-treated cells and that DHA-induced apoptosis was largely inhibited by overexpression of Mcl-1 or RNAi-mediated decrease of Bak and Noxa. In a HCC-xenograft mouse model, the intraperitoneal injection of DHA resulted in significant inhibition of HCC xenograft tumors. Taken together, our data, for the first time, demonstrate the potential antitumor activity of DHA in HCC.
机译：二氢青蒿素（DHA）是从传统中草药青蒿（Artemisia annua L.）中分离出来的青蒿素的半合成衍生物，已显示出对人类癌细胞的抑制作用。然而，尚未研究其对肝细胞癌（HCC）的抗肿瘤能力。在这项研究中，我们证明DHA通过诱导G2 / M细胞周期停滞和凋亡而在体外和体内显着抑制HCC细胞的生长。 p21的诱导和细胞周期蛋白B和CDC25C的抑制导致DHA诱导的G2 / M阻滞。 DHA诱导的细胞凋亡与线粒体膜去极化，细胞色素c的释放，胱天蛋白酶的激活和DNA片段化有关。在DHA处理的细胞中检测到caspase 9和caspase 3的激活，而不是caspase 8的激活。 Z-VAD-FMK预处理的细胞凋亡的减弱提示caspase级联反应的参与。此外，p53促进了由DHA引起的细胞凋亡。 Bcl-2家族蛋白也负责DHA诱导的细胞凋亡。 DHA暴露会降低Mcl-1表达，但会增加Noxa和活性Bak的水平。由于Mcl-1的下降，Bak从Mcl-1 / Bak复合物中释放出来。进一步的研究表明，Mcl-1在DHA处理的细胞中迅速降解，而DHA诱导的细胞凋亡在很大程度上由Mcl-1的过表达或RNAi介导的Bak和Noxa减少所抑制。在HCC异种移植小鼠模型中，腹膜内注射DHA可显着抑制HCC异种移植肿瘤。综上所述，我们的数据首次证明了DHA在肝癌中的潜在抗肿瘤活性。

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