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Amiodarone sensitizes human glioma cells but not astrocytes to TRAIL-induced apoptosis via CHOP-mediated DR5 upregulation

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Author(s)
In Young KimYou Jung KangMi Jin YoonEun Hee KimSeung U KimTaeg Kyu KwonIn Ah KimKyeong Sook Choi
Keimyung Author(s)
Kwon, Taeg Kyu
Department
Dept. of Immunology (면역학)
Journal Title
Neuro-Oncology
Issued Date
2011
Volume
13
Issue
3
Keyword
TRAILapoptosisamiodaronegliomaastrocytes
Abstract
Amiodarone is a widely used anti-arrhythmic drug that
inhibits diverse ion channels, including the Na1/Ca21
exchanger (NCX), L-type Ca21 channels, and Na1
channels. Here, we report that subtoxic doses of
amiodarone and tumor necrosis factor–related apoptosis-
inducing ligand (TRAIL) synergistically induced
apoptosis of various glioma cells. Treatment of
U251MG glioma cells with amiodarone increased intracellular
Ca21 levels and enhanced the expression of the
endoplasmic reticulum (ER) stress-inducible transcription
factor C/EBP homologous protein (CHOP). This
upregulation of CHOP was followed by marked upregulation
of the TRAIL receptor, DR5. Suppression of DR5
expression by small interfering (si) RNAs almost completely
blocked amiodarone/TRAIL-induced apoptosis
in U251MG glioma cells, demonstrating that DR5 is
critical to this cell death. siRNA-mediated CHOP suppression
reduced amiodarone-induced DR5 upregulation
and attenuated the cell death induced by
amiodarone plus TRAIL. In addition, omitting Ca21
from the external medium using ethylene glycol tetraacetic
acid markedly inhibited this cell death, reducing
the protein levels of CHOP and DR5. These results
suggest that amiodarone-induced influx of Ca21 plays
an important role in sensitizing U251MG cells to
TRAIL-mediated apoptosis through CHOP-mediated
DR5 upregulation. Furthermore, subtoxic doses of
bepridil and cibenzoline, two other anti-arrhythmic
drugs with NCX-inhibitor activity, also sensitized
glioma cells to TRAIL-mediated apoptosis, via the upregulation
of both CHOP and DR5. Notably, amiodarone/
TRAIL cotreatment did not induce cell death in
astrocytes, nor did it affect the expression of CHOP or
DR5 in these cells. These results collectively suggest
that a combined regimen of amiodarone plus TRAIL
may offer an effective therapeutic strategy for safely
and selectively treating resistant gliomas.
Keywords: TRAIL, apoptosis, amiodarone, glioma,
astrocytes.
Keimyung Author(s)(Kor)
권택규
Publisher
School of Medicine
Citation
In Young Kim et al. (2011). Amiodarone sensitizes human glioma cells but not astrocytes to TRAIL-induced apoptosis via CHOP-mediated DR5 upregulation. Neuro-Oncology, 13(3), 267–279. doi: 10.1093/neuonc/noq195
Type
Article
ISSN
1522-8517
DOI
10.1093/neuonc/noq195
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/33522
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
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