Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide through glutathione-depletion in imatinib-resistant cells

Heiko Konig, Nicolai Härtel, Beate Schultheis, Michael Schatz, Christian Lorentz, Junia V. Melo, Rüdiger Hehlmann, Andreas Hochhaus, Paul La Rosée

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

The development of resistance to imatinib mesylate may partly depend on high Bcr-Abl-expression levels. Arsenic trioxide (ATO) has Bcr-Abl suppressing activity in vitro. Here we investigated means to improve ATO activity in CML by modulating cellular glutathione (GSH), a key regulator of ATO-activity in malignant disease. Our studies demonstrate that depletion of cellular glutathione using dl-buthionine-[S,R]-sulfoximine (BSO) enhances ATO activity against CML cells. GSH-depletion promotes enhanced Bcr-Abl specific activity of ATO through avid repression of Bcr-Abl protein levels and total cellular Bcr-Abl activity. These data provide a rationale for the clinical development of optimized ATO-based regimens through incorporation of GSH-modulators in CML treatment.

Original languageEnglish (US)
Pages (from-to)838-841
Number of pages4
JournalHaematologica
Volume92
Issue number6
DOIs
StatePublished - Jun 1 2007
Externally publishedYes

Keywords

  • Arsenic
  • Bcr-Abl
  • CML
  • Glutathione
  • Imatinib
  • Resistance

ASJC Scopus subject areas

  • Hematology

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    Konig, H., Härtel, N., Schultheis, B., Schatz, M., Lorentz, C., Melo, J. V., Hehlmann, R., Hochhaus, A., & La Rosée, P. (2007). Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide through glutathione-depletion in imatinib-resistant cells. Haematologica, 92(6), 838-841. https://doi.org/10.3324/haematol.10955