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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

Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York

Requests for reprints: Yongkui Jing, Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, Box 1178, One Gustave L. Levy Place, New York, NY 10029-6547. Phone: 212-241-6775; Fax: 212-996-5787; E-mail: yongkui.jing{at}mssm.edu.

The mechanism of apoptosis induced by treatment with As₂O₃ alone or in combination with buthionine sulfoximine (BSO) was studied in NB4, U937, Namalwa, and Jurkat cells. As₂O₃ at concentrations <2 µmol/L induced apoptosis in NB4 cells and Namalwa cells but not in U937 and Jurkat cells. As₂O₃-induced apoptosis in NB4 cells and Namalwa cells correlated with increase of H₂O₂ and caspase activation without activation of c-Jun NH₂-terminal kinase (JNK). BSO (10 µmol/L) depleted the reduced form of intracellular glutathione without inducing apoptosis but synergized with 1 µmol/L As₂O₃ to induce apoptosis in all four cell lines. This synergy correlated with JNK activation. Treatment with As₂O₃ plus BSO, but not with As₂O₃ 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 As₂O₃ plus BSO. These observations suggest that a DR-mediated pathway activated by JNK is involved in apoptosis induced by treatment with As₂O₃ plus BSO. (Cancer Res 2006; 66(23): 11416-22)

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