Apoptosis induced by extracellular glutathione is mediated by H2O2 production and DNA damage

Paola Perego, Laura Gatti, Nives Carenini, Laura Dal Bo, Franco Zunino

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The biochemical basis of the anti-proliferative effect of exogenous glutathione was investigated in A2780 ovarian carcinoma cells. Previous observations have implicated γ-glutamyl transpeptidase-mediated pro-oxidant reactions as a primary mechanism of the extracellular effects of glutathione. In 2 cell lines (A2780 and IGROV-1), glutathione led to H2O2 production, but only A2780 cells, characterized by low expression of detoxification enzymes, were sensitive to the thiol compound. In A2780 cells, glutathione exposure resulted in DNA single-strand break formation, as measured by alkaline elution. Glutathione-induced DNA damage generated significant levels of apoptosis in A2780 cells, but not in IGROV-I cells. The capability of glutathione to induce apoptosis was associated with cleavage of poly(ADP- ribose)polymerase and with generation of a low-molecular-weight form of the pro-apoptotic protein bax. In A2780 cells, glutathione exposure was followed by p21 and Bax induction and p53 up-regulation, as expected for genotoxic stress. Consistently, analysis of cell-cycle perturbations demonstrated the occurrence of G2M accumulation after exposure to glutathione, similar to what was observed for H2O2. Taken together, these results indicate that the cytotoxic effect of extracellular glutathione, related to membrane metabolism, is mediated by production of H2O2 leading to DNA damage and a cellular response involving p53. These findings might also provide insights into the cellular and molecular determinants of chemosensitivity to DNA damaging agents, as oxidative stress is implicated in p53-dependent apoptosis. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)343-348
Number of pages6
JournalInternational Journal of Cancer
Issue number3
Publication statusPublished - Aug 1 2000

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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