Document Detail


Involvement of reactive oxygen species and caspase-dependent pathway in berberine-induced cell cycle arrest and apoptosis in C6 rat glioma cells.
MedLine Citation:
PMID:  19424587     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cytotoxicity of berberine on C6 rat glioma cells indicated that berberine induced morphological changes and caused cell death through G2/M arrest and apoptosis. While undergoing apoptosis, there was a remarkable accumulation of G2/M cells with the upregulatoin of Wee1 but it also inhibited cyclin B, CDK1 and Cdc25c that led to G2/M arrest. Along with cytotoxicity in C6 cells, several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3 and -8 and DNA fragmentation were induced. Berberine increased the levels of GADD153 and GRP 78 in C6 cells based on the examination of Western blotting and this is a major hallmark of endoplasmic reticulum (ER) stress. We also found that berberine promoted the production of reactive oxygen species and Ca2+ in C6 cells. Western blotting assay also showed that berberine inhibited the levels of anti-apoptotic protein Bcl-2 but increased the levels of pro-apoptotic protein Bax before leading to a decrease in the levels of mitochondrial membrane potential (DeltaPsim) followed by cytochrome c release that caused the activations of capase-9 and -3 for apoptotic occurrence. The caspase-8, -9 and -3 were activated by berberine in C6 cells based on the substrate solution (PhiPhiLux-G1D1, CaspaLux 8-L1D2, CaspaLux 9-M1D2 for caspase-3, -8 and -9, respectively) and analyzed by flow cytometer and each inhibitor of caspase-8, -9 and -3 led to increase the percentage of viable C6 cells after exposure to berberine. This finding was also confirmed by Western blot assay which showed that berberine promoted the active form of caspase-8, -9 and -3. These results demonstrate that the cytotoxicity of berberine in C6 rat glioma cells is attributable to apoptosis mainly through induced G2/M-arrested cells, in an ER-dependent manner, via a mitochondria-dependent caspase pathway regulated by Bax and Bcl-2.
Authors:
Ting-Ching Chen; Kuang-Chi Lai; Jai-Sing Yang; Ching-Lung Liao; Te-Chun Hsia; Guang-Wei Chen; Jen-Jyh Lin; Hui-Ju Lin; Tsan-Hung Chiu; Yih-Jing Tang; Jing-Gung Chung
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  International journal of oncology     Volume:  34     ISSN:  1019-6439     ISO Abbreviation:  Int. J. Oncol.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-08     Completed Date:  2009-08-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9306042     Medline TA:  Int J Oncol     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  1681-90     Citation Subset:  IM    
Affiliation:
Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, ROC.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*
Berberine / pharmacology*
Blotting, Western
Calcium / metabolism
Caspases / antagonists & inhibitors,  metabolism*
Cell Division / drug effects*
Cell Line, Tumor
Cytochromes c / metabolism
DNA Damage / drug effects
Endoplasmic Reticulum / drug effects,  metabolism
Enzyme Inhibitors / pharmacology
Flow Cytometry
G2 Phase / drug effects*
Glioma / metabolism,  pathology*
Membrane Potential, Mitochondrial / drug effects
Mitochondria / drug effects,  metabolism
Proto-Oncogene Proteins c-bcl-2 / metabolism
Rats
Reactive Oxygen Species / metabolism*
bcl-2-Associated X Protein / metabolism
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Proto-Oncogene Proteins c-bcl-2; 0/Reactive Oxygen Species; 0/bcl-2-Associated X Protein; 2086-83-1/Berberine; 7440-70-2/Calcium; 9007-43-6/Cytochromes c; EC 3.4.22.-/Caspases

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