title: Buthionine sulfoximine enhancement of arsenic trioxide-induced apoptosis in leukemia and lymphoma cells is mediated via activation of c-Jun NH2-terminal kinase and up-regulation of death receptors.
abstract: The mechanism of apoptosis induced by treatment with As(2)O(3) alone or in combination with buthionine sulfoximine (BSO) was studied in NB4, U937, Namalwa, and Jurkat cells. As(2)O(3) at concentrations <2 micromol/L induced apoptosis in NB4 cells and Namalwa cells but not in U937 and Jurkat cells. As(2)O(3)-induced apoptosis in NB4 cells and Namalwa cells correlated with increase of H(2)O(2) and caspase activation without activation of c-Jun NH(2)-terminal kinase (JNK). BSO (10 micromol/L) depleted the reduced form of intracellular glutathione without inducing apoptosis but synergized with 1 micromol/L As(2)O(3) to induce apoptosis in all four cell lines. This synergy correlated with JNK activation. Treatment with As(2)O(3) plus BSO, but not with As(2)O(3) alone, increased the levels of death receptor (DR) 5 protein and caspase-8 cleavage. The JNK inhibitor SP600125 inhibited the increase in DR5 protein and attenuated apoptosis induced by treatment with As(2)O(3) plus BSO. These observations suggest that a DR-mediated pathway activated by JNK is involved in apoptosis induced by treatment with As(2)O(3) plus BSO.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029-6547, USA.
authors.forename: Duo
authors.initials: D
authors.lastname: Chen
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Chan
authors.forename: Samuel
authors.initials: S
authors.lastname: Waxman
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Jing
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019169:Jurkat Cells; D007938:Leukemia / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013997:Time Factors; D020298:U937 Cells
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000873:Anthracenes; D001152:Arsenicals; D061945:Caspase Inhibitors; D010087:Oxides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C432165:pyrazolanthrone; D019328:Buthionine Sulfoximine; D006861:Hydrogen Peroxide; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D005978:Glutathione; D000077237:Arsenic Trioxide