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

From the III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany (HK, NH, BS, MS, CL, RH, AH, PLR); Department of Hematology, Imperial College & Hammersmith Hospital London, United Kingdom (JVM)

Correspondence: Paul La Rosée, Klinikum Mannheim gGmbH, III. Medizinische Klinik Theodor-Kutzer-Ufer 7, D- 68167 Mannheim, Germany. E-mail: paul.larosee{at}med3.ma.uniheidelberg.de

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.

Key words: CML, Bcr-Abl, arsenic, glutathione, Imatinib, resistance.