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Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway

Item Type:Article
Title:Arsenic trioxide induces regulated, death receptor-independent cell death through a Bcl-2-controlled pathway
Creators Name:Scholz, C. and Richter, A. and Lehmann, M. and Schulze-Osthoff, K. and Doerken, B. and Daniel, P.T.
Abstract:Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed especially for the treatment of acute promyelocytic leukemia. There and in lymphoid cells, we demonstrated that As2O3 induces cell death in a caspase-2- and -9-independent fashion. Here, we address a potential role of death receptor signaling through the FADD/caspase-8 death-inducing signaling complex in As2O3-induced cell death. In detail, we demonstrate that As2O3 induces cell death independently of caspase-8 or FADD and cannot be blocked by disruption of CD95/Fas receptor ligand interaction. Unlike in death receptor ligation-induced apoptosis, As 2O3-induced cell death was not blocked by the broad-spectrum caspase inhibitor z-VAD-fmk or the caspase-8-specific inhibitor z-IETD-fmk. Nevertheless, As2O3-induced cell death occurred in a regulated manner and was abrogated upon Bcl-2 overexpression. In contrast, As2O3-induced cell demise was neither blocked by the caspase-9 inhibitor z-LEHD-fmk nor substantially inhibited through the expression of a dominant negative caspase-9 mutant. Altogether our data demonstrate that As2O3-induced cell death occurs independently of the extrinsic death receptor pathway of apoptosis. Cell death proceeds entirely via an intrinsic, Bcl-2-controlled mitochondrial pathway that does, however, not rely on caspase-9.
Keywords:Apoptosis, Arsenic trioxide, Caspase-8, CD95/Fas, Death Receptor, FADD
Source:Oncogene
ISSN:0950-9232
Publisher:Nature Publishing Group (U.K.)
Volume:24
Number:47
Page Range:7031-7042
Date:27 October 2005
Official Publication:https://doi.org/10.1038/sj.onc.1208868
PubMed:View item in PubMed

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