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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Anthracenes / pharmacology
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Apoptosis / drug effects*
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Arsenic Trioxide
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Arsenicals / pharmacology*
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Blotting, Western
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Buthionine Sulfoximine / pharmacology*
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Caspase 3 / metabolism
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Caspase Inhibitors
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Synergism
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Enzyme Activation / drug effects
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Glutathione / metabolism
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Humans
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Hydrogen Peroxide / metabolism
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Jurkat Cells
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Leukemia / metabolism
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Leukemia / pathology
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Lymphoma / metabolism
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Lymphoma / pathology
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Oxides / pharmacology*
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
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Time Factors
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U937 Cells
Substances
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Amino Acid Chloromethyl Ketones
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Anthracenes
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Arsenicals
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Caspase Inhibitors
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Oxides
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
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pyrazolanthrone
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Buthionine Sulfoximine
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Hydrogen Peroxide
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JNK Mitogen-Activated Protein Kinases
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Caspase 3
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Glutathione
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Arsenic Trioxide