Arsenic trioxide induces apoptosis via the mitochondrial pathway by upregulating the expression of Bax and Bim in human B cells.
Arsenic trioxide (As2O3) has been approved for the treatment of acute promyelocytic leukemia (APML) and it is a promising candidate for the treatment of patients with lymphoproliferative disorders, such as relapsed or refractory multiple myeloma and myelodysplastic syndromes. The effects of As2O3 on B cells, specifically which do not express Bcl-2, have not been studied. In this study, we have demonstrated that As2O3, at clinically achievable therapeutic concentrations, induces apoptosis in Bcl-2 negative human B cell line Ramos. As2O3-induced apoptosis is associated with reduced mitochondrial transmembrane potential (delta psi), enhanced generation of intracellular reactive oxygen species (ROS), release of cytochrome c and apoptosis-inducing factor (AIF) from mitochondria into cytoplasm, activation of caspases, and upregulation of Bax and Bim expression. Exogenous glutathione (GSH) reverses the As2O3-induced apoptosis in a dose-dependent manner. Altogether, these data indicate that As2O3 induces apoptosis in B cells, regardless of Bcl-2 expression, via the mitochondrial pathway by enhancing oxidative stress.
Baysan
Abdullah
A
Cellular and Molecular Immunology Laboratory, Division of Basic and Clinical Immunology, University of California, Irvine, CA 92697, USA.
Yel
Leman
L
Gollapudi
Sastry
S
Su
Houfen
H
Gupta
Sudhir
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000096:biosynthesis*; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D010087:Oxides / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis*
D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D010087:Oxides; D011518:Proto-Oncogene Proteins; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D000077237:Arsenic Trioxide