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Cellular and Molecular Immunology and Molecular Biology Laboratories, Division of Basic and Clinical Immunology, University of California, Irvine, California 92697

¹ To whom requests for reprints should be addressed, at Medical Sciences I, C-240, University of California, Irvine, CA 92697/ Phone: (949) 824-5818; Fax: (949) 824-4362; E-mail: sgupta{at}uci.edu

Arsenic trioxide (As₂O₃) has been used successfully in the treatment of acute promyelocytic leukemia. However, effects of As₂O₃ in normal peripheral blood T cells have not been studied in detail. The purpose of this study was to investigate whether As₂O₃ would induce apoptosis in normal T cells and therefore may have immunosuppressive side effects. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick end labeling assay, caspase activation by flow cytometry and colorimetric assay, mitochondrial transmembrane potential (_m), intracellular reactive oxygen species (ROS), and intracellular reduced glutathione (GSH) by flow cytometry. The release of cytochrome c and apoptosis-inducing factor (AIF) from the mitochondria was measured by confocal microscopy, and the expression of molecules regulating apoptosis was measured by Western blotting. As₂O₃, at clinically achievable therapeutic concentrations, induces apoptosis in peripheral blood T cells. As₂O₃-induced apoptosis was associated with reduced _m, enhanced generation of intracellular ROS, decreased levels of intracellular GSH, release of cytochrome c and AIF from the mitochondria, activation of caspases, down-regulation of Bcl-2 and Bcl-x_L, and up-regulation of Bax expression. In addition, exogenous GSH protected lymphocytes from As₂O₃-induced apoptosis. Furthermore, overexpression of Bcl-2 inhibited As₂O₃-induced apoptosis and blocked depolarization of _m, generation of ROS, and release of both cytochrome c and AIF. These data indicate that As₂O₃ induces apoptosis in T cells by enhancing oxidative stress and that Bcl-2 appears to play a major role in As₂O₃-induced apoptosis.

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