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Cell line dependence of Bcl-2-induced alteration of glutathione handling

Oncogene volume 19, pages 472–476 (2000)Cite this article

Abstract

Bcl-2 has been associated with both oxidative and antioxidative effects in vivo. Moreover, despite evidence that Bcl-2 is antiapoptotic by virtue of its effect on reactive oxygen species and their scavengers, Bcl-2 exerts its antiapoptotic effects even under anaerobic conditions. The reasons for the variable relationship between Bcl-2 and reactive oxygen species are not clear. The present studies demonstrate that the impact of Bcl-2 on glutathione (GSH) metabolism is cell line-dependent. Bcl-2 overproduction in PC12 cells is associated with increased functional thiol reserves, increased reductive activation of chemotherapeutic prodrugs, and GSH accumulation after treatment with N-acetylcysteine. In contrast, Bcl-2-overproducing MCF-7 breast cancer cells demonstrate neither altered GSH handling nor potentiation of chemotherapeutic prodrug reduction. These findings indicate that the effects of Bcl-2 on GSH handling are millieu-dependent. This could account for the variable effects of Bcl-2 in in vivo systems. Furthermore, since our previous studies have demonstrated that reduction-dependent prodrugs may be useful chemotherapeutic agents against tumors that demonstrate altered GSH handling, screening in vitro for alteration of GSH handling may predict responsiveness of such tumors to these reduction-dependent agents.

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Acknowledgements

The authors wish to acknowledge the expert technical assistance of Karen D Nylander. This work was funded by grants CA74289 from the National Institutes of Health and DAMD17-97-1-7247 from the Department of the Army. YY Tyurina was partly supported by the International Neurological Science Fellowship Program #F05 NS 10669 administered by NIH/NINDS in collaboration with WHO, Unit of Neuroscience, Division of Mental Health and Prevention of Substance Abuse.

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Authors and Affiliations

  1. Department of Pediatrics, University of Pittsburgh, Pittsburgh, 15213, Pennsylvania, PA, USA

    N F Schor

  2. Department of Neurology, University of Pittsburgh, Pittsburgh, 15213, Pennsylvania, PA, USA

    N F Schor

  3. Department of Pharmacology, University of Pittsburgh, Pittsburgh, 15213, Pennsylvania, PA, USA

    N F Schor & V E Kagan

  4. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, 15213, Pennsylvania, PA, USA

    Y Y Tyurina & V E Kagan

  5. Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, PA, USA

    N F Schor, Y Y Tyurina & V E Kagan

  6. Department of Medicine, University of Chicago, Chicago, 60637, Illinois, IL, USA

    C M Rudin, A-R Hartman & C B Thompson

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Schor, N., Rudin, C., Hartman, AR. et al. Cell line dependence of Bcl-2-induced alteration of glutathione handling. Oncogene 19, 472–476 (2000). https://doi.org/10.1038/sj.onc.1203324

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