Haematologica (Jun 2007)

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

DOI
https://doi.org/10.3324/haematol.10955
Journal volume & issue
Vol. 92, no. 6

Abstract

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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.