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Gliotoxin enhances radiotherapy via inhibition of radiation‐induced GADD45a, p38, and NFκB activation
Author(s) -
Hur JungMu,
Yun HyeJeong,
Yang SooHyung,
Lee WooYiel,
Joe Minho,
Kim Dongho
Publication year - 2008
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21776
Subject(s) - gliotoxin , apoptosis , radiosensitivity , p38 mitogen activated protein kinases , reactive oxygen species , chemistry , annexin , nf κb , programmed cell death , microbiology and biotechnology , cell culture , cancer research , signal transduction , biology , biochemistry , radiation therapy , mapk/erk pathway , immunology , medicine , aspergillus fumigatus , genetics
The purpose of the study was to elucidate the mechanism underlying the enhancement of radiosensitivity to 60 Co γ‐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 (NFκB) activated in irradiated cells was inhibited by Gliotoxin. Specific inhibitors of p38 kinase, SB203580, significantly inhibited NFκB 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‐NFκB 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. J. Cell. Biochem. 104: 2174–2184, 2008. © 2008 Wiley‐Liss, Inc.