Silibinin Inhibits Glioma Cell Proliferation via Ca2+/ROS/MAPK-Dependent Mechanism In Vitro and Glioma Tumor Growth In Vivo
Silibinin Inhibits Glioma Cell Proliferation via Ca2+/ROS/MAPK-Dependent Mechanism In Vitro and Glioma Tumor Growth In Vivo
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DOI：
10.1007/s11064-009-9935-6
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发表时间：
2009-08-01
影响因子：
4.4
通讯作者：
Kim, Yong Keun
中科院分区：
文献类型：
--
作者：
Kim, Kwang Won;Choi, Chang Hwa;Kim, Yong Keun
水飞蓟宾是一种黄酮类化合物，其抗癌活性已在多种癌细胞类型中得到证实。然而，神经胶质瘤的潜在机制和体内疗效尚未阐明。本研究旨在探讨水飞蓟宾在体外对胶质瘤细胞增殖的影响，以及水飞蓟宾在体内是否抑制肿瘤生长。水飞蓟宾以剂量和时间依赖性方式抑制增殖，这主要归因于细胞死亡。水飞蓟宾诱导细胞内Ca 2+瞬时增加，随后增加活性氧（ROS）的产生。EGTA、钙蛋白酶抑制剂和抗氧化剂（N-乙酰半胱氨酸和Trolox）可阻止水飞蓟宾诱导的细胞死亡。蛋白质印迹分析表明，水飞蓟宾还诱导细胞外信号调节激酶、p38激酶和c-Jun N-末端激酶的ROS依赖性激活。这些激酶的抑制剂阻止了水飞蓟宾诱导的细胞死亡。水飞蓟宾引起caspase激活，caspase抑制剂阻止水飞蓟宾诱导的细胞死亡。水飞蓟宾治疗也减少了胶质瘤细胞的迁移。在具有皮下U87 MG胶质瘤细胞的动物中口服施用水飞蓟宾减少肿瘤体积。随后的肿瘤组织分析显示Ki-67阳性细胞减少，TUNEL阳性细胞增加，半胱天冬酶激活。这些结果表明，水飞蓟宾通过Ca 2 +/ROS/MAPK介导的途径在体外诱导caspase依赖性细胞死亡，并在体内抑制胶质瘤生长。这些数据表明，水飞蓟宾可能作为一个潜在的治疗剂的恶性胶质瘤。
Anticancer activity of silibinin, a flavonoid, has been demonstrated in various cancer cell types. However, the underlying mechanism and in vivo efficacy in glioma were not elucidated. The present study was undertaken to determine the effect of silibinin on glioma cell proliferation in vitro and to examine whether silibinin inhibits tumor growth in vivo. Silibinin resulted in inhibition of proliferation in a dose- and time-dependent manner, which was largely attributed to cell death. Silibinin induced a transient increase in intracellular Ca2+ followed by an increase in reactive oxygen species (ROS) generation. The silibinin-induced cell death was prevented by EGTA, calpain inhibitor and antioxidants (N-acetylcysteine and Trolox). Western blot analysis showed that silibinin also induced ROS-dependent activation of extracellular signal-regulated kinase, p38 kinase, and c-Jun N-terminal kinase. Inhibitors of these kinases prevented the silibinin-induced cell death. Silibinin caused caspase activation and the silibinin-induced cell death was prevented by caspase inhibitors. Glioma cell migration was also decreased by silibinin treatment. Oral administration of silibinin in animals with subcutaneous U87MG glioma cells reduced tumor volume. Subsequent tumor tissue analysis showed a decrease in Ki-67 positive cells, an increase in TUNEL-positive cells, and caspase activation. These results indicate that silibinin induces a caspase-dependent cell death via Ca2+/ROS/MAPK-mediated pathway in vitro and inhibits glioma growth in vivo. These data suggest that silibinin may serve as a potential therapeutic agent for malignant human gliomas.