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 Psim) 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 kappaB-alpha phosphorylation strongly decreased, and NF-kappaB translocation to the nucleus was abrogated. Expression of the antiapoptotic protein Bcl-X-L, whose promoter is NF-kappaB dependent, was down-regulated. The collapse of Delta Psim and the release of cytochrome c to the cytosol resulted in the activation of caspase-3, as demonstrated by the cleavage of PARR A specific caspase-3 Inhibitor (Ac-DEVD-CHO) could reverse this phenotype. The antiapoptotic factor Bcl-2 was then cleaved, converting ft to a Sax-like death effector. These results demonstrated that arsenic trioxide Induces apoptosis In HTLV-1- and -2-infected cells through activation of the caspase pathway. (C) 2001 by The American Society of Hematology.