N-Acetyl cysteine and caﬀeic acid phenethyl ester
sensitize astrocytoma cells to Fas-mediated cell death
in a redox-dependent manner
, Young-Hee Han
, Chulhee Choi
Laboratory of Computational Cell Biology, Department of Brain and Bioengineering, Korea Advanced Institute of Science
and Technology (KAIST), 373-1, Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST),
Daejeon 305-701, Republic of Korea
KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea
Received 21 March 2007; received in revised form 25 June 2007; accepted 2 July 2007
In this study, we investigated the role of reactive oxygen species (ROS) in Fas-induced cell death in human astrocytoma
cells. Fas activation increased intracellular ROS levels in a NADPH oxidase- and caspase-dependent manner. ROS inhib-
itors such as N-acetyl cysteine (NAC) and caﬀeic acid phenethyl ester (CAPE) dramatically sensitized astocytoma cells to
Fas-induced loss of mitochondrial transmembrane potential and subsequent cell death, which were abrogated by pretreat-
ment with z-VAD-fmk, a broad-spectrum caspase inhibitor. These results collectively indicate that NAC and CAPE sen-
sitize astrocytoma cells to Fas-induced apoptosis in a redox-dependent manner, suggesting a potential use in the treatment
of malignant brain tumors.
Ó 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: Apoptosis; Caﬀeic acid phenethyl ester; Fas; Reactive oxygen species; N-Acetyl cysteine
Fas (CD95 or APO-1), a member of the TNF/
NGF receptor family, induces a caspase-dependent
apoptotic death in various transformed cells [1–3].
Fas ligation with natural ligand or agonistic anti-
Fas antibody is followed by recruitment of pro-
apoptotic adaptor molecules such as Fas-associated
death domain (FADD) to transduce apoptotic sig-
nals through the caspase cascades . In some cells
(type 1), Fas does eﬃciently activate caspase-8 and
subsequently caspase-3 or -7, while in other types
(type 2) Fas-induced activation of eﬀector caspases
and apoptosis were mediated by cytochrome C
release from mitochondria and inhibited by overex-
pression of anti-apoptotic bcl-2 family members
. It has been proposed that BCR-induced Fas
0304-3835/$ - see front matter Ó 2007 Elsevier Ireland Ltd. All rights reserved.
Corresponding author. Address: Laboratory of Computa-
tional Cell Biology, Department of Brain and Bioengineering,
Korea Advanced Institute of Science and Technology (KAIST),
373-1, Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic
of Korea. Tel.: 82 42 869 4321; fax: +82 42 869 4380.
E-mail address: email@example.com (C. Choi).
URL: http://ccbio.kaist.ac.kr (C. Choi).
Cancer Letters 257 (2007) 79–86