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.
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.
Mahieux
R
R
Unité d'Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur, Paris, France. rmahieux@pasteur.fr
Pise-Masison
C
C
Gessain
A
A
Brady
J N
JN
Olivier
R
R
Perret
E
E
Misteli
T
T
Nicot
C
C
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D015367:Human T-lymphotropic virus 2 / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins; D016898:Interferon-alpha / Q000494:pharmacology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology* / Q000821:virology; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000648:ultrastructure; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D001152:Arsenicals; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016898:Interferon-alpha; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010087:Oxides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000077237:Arsenic Trioxide