Ecology-based screen identifies new metabolites from a Cordyceps-colonizing fungus as cancer cell proliferation inhibitors and apoptosis inducers
Ecology-based screen identifies new metabolites from a Cordyceps-colonizing fungus as cancer cell proliferation inhibitors and apoptosis inducers
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基于生态学的筛选鉴定出来自冬虫夏草定殖真菌的新代谢物作为癌细胞增殖抑制剂和细胞凋亡诱导剂
DOI：
10.1111/j.1365-2184.2009.00636.x
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发表时间：
2009-12-01
影响因子：
8.5
通讯作者：
Ye, X.
中科院分区：
文献类型：
--
作者：
Chen, Y.;Guo, H.;Ye, X.
目的：利用生态学方法，从虫草定殖真菌中鉴定新的抗癌药物。探讨其抗细胞增殖机制，并在体内评价其抗肿瘤作用。材料与方法：将冬虫夏草定殖真菌提取物作用于HeLa细胞，分离活性提取物获得抗肿瘤代谢物；用质谱和核磁共振谱分析了它们的结构。流式细胞术评价细胞周期分析。采用C57BL/6J小鼠进行肿瘤形成实验。结果：基于生态学的考虑，所选提取物进行了初步的抗肿瘤筛选。生物测定指导下的活性提取物分离得到两种新的表聚硫代二氧哌嗪，命名为gliocladicillins A(1)和B(2)。(A) 1和B(2)抑制HeLa， HepG2和MCF-7肿瘤细胞的生长。进一步的研究表明，两种制剂均以剂量依赖的方式将细胞周期阻滞在G(2)/M期，并通过上调p53、p21和cyclin B的表达以及激活caspase -8、-9和-3诱导细胞凋亡。这些数据表明gliocladicillins A(1)和B(2)通过外在和内在途径诱导肿瘤细胞凋亡。此外，体内研究表明，它们对植入免疫缺陷小鼠的黑色素瘤B16细胞的细胞群生长有显著的抑制作用。结论：Gliocladicillins A(1)和B(2)是体外和体内有效的抗肿瘤药物，其临床应用潜力有待进一步评估。
Objectives:This study aims to identify new anti-cancer agents from Cordyceps-colonizing fungi, using an ecology-based approach. It also aims to explore their anti-cell proliferative mechanisms, and to evaluate their anti-tumour effects in vivo.Materials and methods:Extracts from Cordyceps-colonizing fungi were tested on HeLa cells, and active extracts were separated to obtain anti-tumour metabolites; their structures were elucidated by mass and nuclear magnetic resonance spectroscopy. Cell cycle analysis was evaluated using flow cytometry. Tumour formation assays were performed using C57BL/6J mice.Results:Based on ecological considerations, the selected extracts were subjected to initial anti-tumour screening. Bioassay-guided fractionation of the active extract afforded two new epipolythiodioxopiperazines, named gliocladicillins A (1) and B (2). (A) 1 and B (2) inhibited growth of HeLa, HepG2 and MCF-7 tumour cells. Further study demonstrated that both preparations arrested the cell cycle at G(2)/M phase in a dose-dependent manner, and induced apoptosis through up-regulation of expression of p53, p21, and cyclin B, and activation of caspases-8, -9 and -3. These data imply that gliocladicillins A (1) and B (2) induce tumour cell apoptosis through both extrinsic and intrinsic pathways. In addition, in vivo studies showed that they displayed significant inhibitory effects on cell population growth of melanoma B16 cells imlanted into immunodeficient mice.Conclusions:Gliocladicillins A (1) and B (2) are effective anti-tumour agents in vitro and in vivo and should be further evaluated for their potential in clinical use.