Open AccessEcology‐based screen identifies new metabolites from a Cordyceps ‐colonizing fungus as cancer cell proliferation inhibitors and apoptosis inducers
Author(s) -
Chen Y.,
Guo H.,
Du Z.,
Liu X.Z.,
Che Y.,
Ye X.
Publication year - 2009
Publication title -
cell proliferation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.647
H-Index - 74
eISSN - 1365-2184
pISSN - 0960-7722
DOI - 10.1111/j.1365-2184.2009.00636.x
Subject(s) - hela , apoptosis , cell cycle , in vivo , biology , flow cytometry , cell growth , cancer cell , cordyceps , cell cycle checkpoint , cell , population , cordyceps militaris , cancer research , cancer , biochemistry , microbiology and biotechnology , botany , medicine , genetics , environmental health
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.