Document Detail


Gliotoxin enhances radiotherapy via inhibition of radiation-induced GADD45a, p38, and NFkappaB activation.
MedLine Citation:
PMID:  18425744     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The purpose of the study was to elucidate the mechanism underlying the enhancement of radiosensitivity to 60Co gamma-irradiation in human hepatoma cell line HepG2 pretreated with gliotoxin. Enhancement of radiotherapy by gliotoxin was investigated in vitro with human hepatoma HepG2 cell line. Apoptosis related proteins were evaluated by Western blotting. Annexin V/PI and reactive oxygen species (ROS) were quantified by Flow Cytometric (FACS) analysis. Gliotoxin (200 ng/ml) combined with radiation (4 Gy) treated cells induced apoptosis. Cells treated with gliotoxin (200 ng/ml) prior to irradiation at 4 Gy induced the expression of bax and nitric oxide (NO). The gliotoxin-irradiated cells also increased caspase-3 activation and ROS. Gadd45a, p38, and nuclear factor kappa B (NFkappaB) activated in irradiated cells was inhibited by Gliotoxin. Specific inhibitors of p38 kinase, SB203580, significantly inhibited NFkappaB activation and increased the cytotoxicity effect in cells exposed to gliotoxin combined with irradiation. However, SB203580 did not suppress the activation of Gadd45a in irradiated cells. Gliotoxin inhibited anti-apoptotic signal pathway involving the activation of Gadd45a-p38-NFkappaB mediated survival pathway that prevent radiation-induced cell death. Therefore, gliotoxin, blocking inflammation pathway and enhancing irradiation-induced apoptosis, is a promising agent to increase the radiotherapy of tumor cells.
Authors:
Jung-Mu Hur; Hye-Jeong Yun; Soo-Hyung Yang; Woo-Yiel Lee; Min-Ho Joe; Dongho Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cellular biochemistry     Volume:  104     ISSN:  1097-4644     ISO Abbreviation:  J. Cell. Biochem.     Publication Date:  2008 Aug 
Date Detail:
Created Date:  2008-07-29     Completed Date:  2008-10-15     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8205768     Medline TA:  J Cell Biochem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2174-84     Citation Subset:  IM    
Affiliation:
Radiation Research Center for Bio-Technology, Korea Atomic Energy Research Institute, Jeongeup 580-185, South Korea.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cell Survival / drug effects
Enzyme Activation / drug effects
Gamma Rays*
Gliotoxin / pharmacology*
Humans
Models, Biological
NF-kappa B / metabolism*
Nitric Oxide / metabolism
Nuclear Proteins / metabolism*
Radiation Tolerance* / drug effects
Reactive Oxygen Species / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism*
Chemical
Reg. No./Substance:
0/Cell Cycle Proteins; 0/GADD45A protein, human; 0/NF-kappa B; 0/Nuclear Proteins; 0/Reactive Oxygen Species; 10102-43-9/Nitric Oxide; 67-99-2/Gliotoxin; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases

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