Effect of glutathione depletion on antitumor drug toxicity in U-937 human promonocytic cells: the role of intracellular oxidation - apoptosis and necrosis - Abstract

Alternative Medicine Review, Dec, 2001

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. Pre-incubation with the GSH synthesis inhibitor L-buthionine-[S,R]-sulfoximine always potentiated peroxide accumulation. However, while 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 pre-incubation 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 H(2)O(2) 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 (DeltaPsim), 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 DeltaPsim 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.

Troyano A, Fernandez C, Sancho P, et al. J Biol Chem 2001; [epub ahead of print].