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

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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 (ΔΨm) 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. IκB-α phosphorylation strongly decreased, and NF-κB translocation to the nucleus was abrogated. Expression of the antiapoptotic protein Bcl-XL, whose promoter is NF-κB dependent, was down-regulated. The collapse of ΔΨm 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.