Xanthohumol Induces Apoptosis in Human Malignant Glioblastoma Cells by Increasing Reactive Oxygen Species and Activating MAPK Pathways
Xanthohumol Induces Apoptosis in Human Malignant Glioblastoma Cells by Increasing Reactive Oxygen Species and Activating MAPK Pathways
复制标题
DOI：
10.1021/np200390x
复制
发表时间：
2011-12-01
影响因子：
5.1
通讯作者：
Piacente, Sonia
中科院分区：
文献类型：
--
作者：
Festa, Michela;Capasso, Anna;Piacente, Sonia
研究了生物活性异戊二烯化查耳酮和潜在抗癌剂黄腐酚（1）对T98 G人恶性胶质母细胞瘤细胞系凋亡的影响。化合物1通过以时间和浓度依赖性方式诱导细胞凋亡来降低T98 G细胞的存活率。1诱导的细胞凋亡与caspase-3、caspase-9和PARP裂解的激活相关，并由线粒体途径介导，如线粒体去极化、细胞色素c释放和抗凋亡Bcl-2蛋白的下调。黄腐酚诱导细胞内活性氧（ROS），这种作用可通过抗氧化剂N-乙酰-L-半胱氨酸（NAC）预处理来降低。细胞内ROS的产生似乎是必不可少的线粒体途径的激活和诱导细胞凋亡暴露后1。通过ERK 1/2和p38磷酸化测定，1处理引起的氧化应激与MAPK活化相关。使用NAC来抑制ROS产生，从而减弱ERK 1/2和p38的磷酸化。1处理后，ROS提供了一个特定的环境，导致MAPK诱导的细胞死亡，这种作用被ERK 1/2特异性抑制剂PD 98059降低，并被p38抑制剂SB 203580部分抑制。这些结果表明，黄腐酚（1）是一个潜在的化疗药物治疗多形性胶质母细胞瘤。
The effect of the biologically active prenylated chalcone and potential anticancer agent xanthohumol (1) has been investigated on apoptosis of the T98G human malignant glioblastoma cell line. Compound 1 decreased the viability of T98G cells by induction of apoptosis in a time- and concentration-dependent manner. Apoptosis induced by 1 was associated with activation of caspase-3, caspase-9, and PARP cleavage and was mediated by the mitochondrial pathway, as exemplified by mitochondrial depolarization, cytochrome c release, and downregulation of the antiapoptotic Bcl-2 protein. Xanthohumol induced intracellular reactive oxygen species (ROS), an effect that was reduced by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC). Intracellular ROS production appeared essential for the activation of the mitochondrial pathway and induction of apoptosis after exposure to 1. Oxidative stress due to treatment with 1 was associated with MAPK activation, as determined by ERK1/2 and p38 phosphorylation. Phosphorylation of ERK1/2 and p38 was attenuated using NAC to inhibit ROS production. After treatment with 1, ROS provided a specific environment that resulted in MAPK-induced cell death, with this effect reduced by the ERK1/2 specific inhibitor PD98059 and partially inhibited by the p38 inhibitor SB203580. These findings suggest that xanthohumol (1) is a potential chemotherapeutic agent for the treatment of glioblastoma multiforme.