Ecology-based screen identifies new metabolites from a Cordyceps-colonizing fungus as cancer cell proliferation inhibitors and apoptosis inducers.
OBJECTIVE
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.


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 implanted 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.
Chen
Y
Y
Center for Molecular Immunology, CAS Key Laboratory of Pathogenic Microbiology and Immunology, Chinese Academy of Sciences, Beijing, China. markus.scholz@imise.uni-leipzig.de
Guo
H
H
Du
Z
Z
Liu
X-Z
XZ
Che
Y
Y
Ye
X
X
D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D032661:Cordyceps / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004463:Ecology; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL
D000970:Antineoplastic Agents; D020169:Caspases