Arsenic trioxide induces apoptosis in human T-cell leukemia virus type 1- and type 2-infected cells by a caspase-3-dependent mechanism involving Bcl-2 cleavage.

Abstract

Treatment of patients with adult T-cell leukemia-lymphoma (ATLL) using conventional chemotherapy has limited benefit because human T-cell leukemia virus type 1 (HTLV-1) cells are resistant to most apoptosis-inducing agents. The recent report that arsenic trioxide induces apoptosis in HTLV-1-transformed cells prompted investigation of the mechanism of action of this drug in HTLV-1 and HTLV-2 interleukin-2-independent T cells and in HTLV-1-immortalized cells or in ex vivo ATLL samples. Fluorescence-activated cell sorter analysis, fluorescence microscopy, and measures of mitochondrial membrane potential (Delta Psi m) demonstrated that arsenic trioxide alone was sufficient to induce programmed cell death in all HTLV-1 and -2 cells tested and in ATLL patient samples. I kappa B-alpha phosphorylation strongly decreased, and NF-kappa B translocation to the nucleus was abrogated. Expression of the antiapoptotic protein Bcl-X(L), whose promoter is NF-kappa B dependent, was down-regulated. The collapse of Delta Psi m and the release of cytochrome c to the cytosol resulted in the activation of caspase-3, as demonstrated by the cleavage of PARP. A specific caspase-3 inhibitor (Ac-DEVD-CHO) could reverse this phenotype. The antiapoptotic factor Bcl-2 was then cleaved, converting it to a Bax-like death effector. These results demonstrated that arsenic trioxide induces apoptosis in HTLV-1- and -2-infected cells through activation of the caspase pathway.

• Authors: R Mahieux, C Pise-Masison, A Gessain, J N Brady, R Olivier, E Perret, T Misteli, C Nicot
• Journal: Blood (Blood) Vol. 98 Issue 13 Pg. 3762-9 (Dec 15 2001) ISSN: 0006-4971 [Print] United States
• PMID: 11739184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arsenicals
• BAX protein, human
• BCL2L1 protein, human
• Cytochrome c Group
• DNA-Binding Proteins
• I-kappa B Proteins
• Interferon-alpha
• NF-kappa B
• NFKBIA protein, human
• Oxides
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• bcl-X Protein
• NF-KappaB Inhibitor alpha
• CASP3 protein, human
• Caspase 3
• Caspases
• Arsenic Trioxide

Topics

• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Caspase 3
• Caspases (metabolism)
• Cell Line, Transformed
• Cell Nucleus (metabolism)
• Cytochrome c Group (metabolism)
• DNA-Binding Proteins (metabolism)
• Flow Cytometry
• Human T-lymphotropic virus 1 (physiology)
• Human T-lymphotropic virus 2 (physiology)
• Humans
• I-kappa B Proteins
• Interferon-alpha (pharmacology)
• Leukemia-Lymphoma, Adult T-Cell (pathology, virology)
• Membrane Potentials
• Microscopy, Fluorescence
• Mitochondria (ultrastructure)
• NF-KappaB Inhibitor alpha
• NF-kappa B (metabolism)
• Oxides (pharmacology)
• Phosphorylation
• Proto-Oncogene Proteins (analysis)
• Proto-Oncogene Proteins c-bcl-2 (analysis, metabolism)
• Tumor Suppressor Protein p53 (analysis)
• bcl-2-Associated X Protein
• bcl-X Protein