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Effect of
Glutathione Depletion on Antitumor Drug Toxicity (Apoptosis and Necrosis)
in U-937 Human Promonocytic Cells
Alfonso Troyano, Carlos Fernandez, Patricia Sancho, Elena de Blas, and
Patricio Aller
The Journal of Biological Chemistry. Vol. 276, No. 50, Issue of December
14, pp. 47107–47115, 2001.
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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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