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J. Biol. Chem., Vol. 276, Issue 50, 47107-47115, December 14, 2001

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Effect of Glutathione Depletion on Antitumor Drug Toxicity (Apoptosis and Necrosis) in U-937 Human Promonocytic Cells
THE ROLE OF INTRACELLULAR OXIDATION^*

Alfonso Troyano^§, Carlos Fernández, Patricia Sancho^¶, Elena de Blas, and Patricio Aller^**

From the  Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, and ^¶ Departamento de Biología Celular y Genética, Universidad de Alcalá, Madrid 28006, Spain

Treatment with the DNA topoisomerase inhibitors etoposide, doxorubicin, and camptothecin, and with the alkylating agents cisplatin and melphalan, caused peroxide accumulation and apoptosis in U-937 human promonocytic cells. Preincubation with the reduced glutathione (GSH) synthesis inhibitor L-buthionine-(S,R)-sulfoximine (BSO) always potentiated peroxide accumulation. However, although GSH depletion potentiated the toxicity of cisplatin and melphalan, occasionally switching the mode of death from apoptosis to necrosis, it did not affect the toxicity of the other antitumor drugs. Hypoxia or preincubation with antioxidant agents attenuated death induction, apoptotic and necrotic, by alkylating drugs. The generation of necrosis by cisplatin could not be mimicked by addition of exogenous H₂O₂ instead of BSO and was not adequately explained by caspase inactivation nor by a selective fall in ATP content. Treatment with cisplatin and melphalan caused a late decrease in mitochondrial transmembrane potential (m), which was much greater during necrosis than during apoptosis. The administration of the antioxidant agents N-acetyl-L-cysteine and butylated hydroxyanisole after pulse treatment with cisplatin or melphalan did not affect apoptosis but attenuated necrosis. Under these conditions, both antioxidants attenuated the necrosis-associated m decrease. These results indicate that oxidation-mediated alterations in mitochondrial function regulate the selection between apoptosis and necrosis in alkylating drug-treated human promonocytic cells.

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