Synergistic antitumor activity of oridonin and arsenic trioxide on hepatocellular carcinoma cells
Synergistic antitumor activity of oridonin and arsenic trioxide on hepatocellular carcinoma cells
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冬凌草甲素与三氧化二砷对肝癌细胞的协同抗肿瘤活性
DOI：
10.3892/ijo.2011.1210
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发表时间：
2012-01-01
影响因子：
5.2
通讯作者：
Hua, Zi-Chun
中科院分区：
文献类型：
--
作者：
Chen, Guo;Wang, Ke;Hua, Zi-Chun
虽然三氧化二砷（As_2O_3）已成功地用于治疗急性早幼粒细胞白血病（APL）患者，但实体瘤细胞对该治疗的敏感性远低于APL细胞。在11期临床试验中，As 2 O3单药治疗肝细胞癌（HCC）的效果不佳，这表明需要新的治疗方法来增强治疗效果。本研究发现，从中药冬凌草中提取的二萜类化合物冬凌草甲素能显著增强As_2O_3诱导的肝癌细胞凋亡。这两种药物联合的协同促凋亡作用导致细胞内活性氧（ROS）水平和N-乙酰-L-半胱氨酸（NAC）增加。一种含硫醇的抗氧化剂，能够完全阻断这种作用。联合处理诱导ROS依赖性的线粒体膜电位（MMP）降低，以及Bax和细胞色素C的重新定位。此外，冬凌草甲素还能显著增加As_2O_3引起的细胞内Ca ~（2+）超载。此外，冬凌草甲素和As 2 O3联合处理可诱导ROS介导的Akt和XIAP表达下调，并抑制NF-κ B B活化。与体内单药治疗相比，两种药物组合增强了小鼠HCC模型中的肿瘤抑制活性。这些结果表明，冬凌草甲素可以提高肝癌细胞对As_2O_3治疗的敏感性，并将促进肝癌患者As_2O_3治疗的优化。
Although arsenic trioxide (As2O3) has been successfully employed in treatment of patients with APL (acute promyelocytic leukemia), the sensitivity of solid tumor cells to this treatment was much lower than APL cells. The single agent of As2O3 was inefficient for treatment of hepatocellular carcinoma (HCC) in phase 11 trial demonstrating that new modalities of treatment with enhanced therapeutic effect are needed. In this study, we showed that oridonin, a diterpenoid isolated from traditional Chinese medicine Rabdosia rubescences, greatly potentiated apoptosis induced by As2O3 in hepatocellular carcinoma cells. The synergistic pro-apoptosis effect of combination of these two drugs led to increase in intracellular reactive oxygen species (ROS) level and N-acetyl-L-cysteine (NAC). a thiol-containing anti-oxidant, was able to completely block the effect. The combination treatment induced ROS-dependent decrease in mitochondrial membrane potential (MMP) decrease, and relocation of Bax and cytochrome C. Besides, oridonin dramatically increased the intracellular Ca2+ overload triggered by As2O3. Furthermore, the co-treatment of oridonin and As2O3 induced ROS-mediated down-regulation of Akt and XIAP, and inhibition of NF-kappa B activation. The two drug combination enhanced tumor suppression activity in murine HCC model compared with single agent treatment in vivo. These findings demonstrate that oridonin can sensitize hepatocellular carcinoma cells to As2O3 treatment and will facilitate the optimization of As2O3 therapy for HCC patients.