The cell-specific anti-proliferative effect of reduced glutathione is mediated by γ-glutamyl transpeptidase-dependent extracellular pro-oxidant reactions

Paola Perego, Aldo Paolicchi, Roberto Tongiani, Alfonso Pompella, Patrizia Tonarelli, Nives Carenini, Simona Romanelli, Franco Zunino

Research output: Contribution to journalArticle

Abstract

We have shown earlier that extracellular GSH can exert a cell-specific growth-inhibitory effect on human tumor cells. In the present study, 2 human ovarian carcinoma cell lines (A2780 and IGROV-1) were used to investigate the biochemical basis of the GSH growth-inhibitory effect. Whereas cells were resistant, A2780 cells were sensitive to a 1 hr exposure to GSH, as assessed by the growth inhibition assay. Analysis of relevant GSH-dependent enzymes indicated that A2780 cells had low level of GSH S-transferase, glutathione reductase and γ-glutamyl transpeptidase (γ-GT) activities in comparison with those of IGROV-1 cells, and GSH peroxidase activity was undetectable in A2780 cells. The GSH effect was reversed by catalase and by dithiothreitol, indicating the occurrence of oxidative phenomena resulting in the impairment of critical cellular thiols. Indeed treatment of cells with H2O2 also resulted in growth inhibition, which was more marked in A2780 cells. The γ- glutamyl acceptor glycylglycine, a cosubstrate for γ-GT, potentiated the growth-inhibitory effect of GSH, which in contrast was decreased by the γ- GT inhibitors, serine-borate complex and acivicin, suggesting that the production of reactive forms of oxygen (probably H2O2) was mediated by cysteinyl-glycine after GSH hydrolysis. The results support that the growth- inhibitory effect of low GSH concentration is the result of oxidative damage related to extracellular GSH metabolism.

Original languageEnglish
Pages (from-to)246-250
Number of pages5
JournalInternational Journal of Cancer
Volume71
Issue number2
DOIs
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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