Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide (Trisenox) through glutathione-depletion in imatinib-resistant cells.
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.
Konig
Heiko
H
III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg, Mannheim, Germany.
Härtel
Nicolai
N
Schultheis
Beate
B
Schatz
Michael
M
Lorentz
Christian
C
Melo
Junia V
JV
Hehlmann
Rüdiger
R
Hochhaus
Andreas
A
La Rosée
Paul
P
D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001549:Benzamides; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects*; D005978:Glutathione / Q000032:analysis* / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010087:Oxides / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
D001152:Arsenicals; D001549:Benzamides; D010087:Oxides; D010879:Piperazines; D011743:Pyrimidines; D019328:Buthionine Sulfoximine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D005978:Glutathione; D000077237:Arsenic Trioxide