Arsenic trioxide induces apoptosis preferentially in B-CLL cells of patients with unfavourable prognostic factors including del17p13.
In the last decade, arsenic trioxide (As2O3) has been used very successfully to treat acute promyelocytic leukaemia (APL). Much less is known about the effectiveness of As2O3 in other neoplastic disorders. In this paper, we report that after 18 h in vitro treatment with 4 microM As2O3, 75+/-18% of B cell chronic lymphocytic leukaemia (B-CLL) cells (n=52) underwent apoptosis. It is important to note that B-CLL cells harboring a deletion of chromosome 17p13, which predisposes to fludarabine resistance and has been identified as an important negative predictor of clinical outcome, were more susceptible to As2O3 toxicity than cells lacking this aberration. Furthermore, unfavourable risk profiles such as unmutated IgVH status, high CD38 expression and prior treatment were associated with significantly higher sensitivity of B-CLL cells to As2O3. As2O3 also preferentially killed B-CLL cells compared to B cells from healthy age-matched controls. Molecular analysis revealed that basal superoxide dismutase activity was positively correlated with the pro-apoptotic activity of As2O3 pointing to a role of reactive oxygen species in cell death induction. The high activity of As2O3 in B-CLL cells from high-risk patients makes it a promising drug for high-risk and/or fludarabine-refractory B-CLL patients.
Merkel
Olaf
O
Laboratory for Immunological and Molecular Cancer Research, IIIrd Medical Department with Hematology, Medical Oncology, Hemostaseology, Rheumatology and Infectiology, Paracelsus Medical University Salzburg, Salzburg, Austria. o.merkel@salk.at
Heyder
Christoph
C
Asslaber
Daniela
D
Hamacher
Frank
F
Tinhofer
Inge
I
Holler
Claudia
C
Stöcher
Markus
M
Prokesch
Andreas
A
Papak
Christine
C
Scheideler
Marcel
M
Trajanoski
Zlatko
Z
Greil
Richard
R
D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002872:Chromosome Deletion; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000201:enzymology / Q000473:pathology*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology* / Q000633:toxicity; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
D001152:Arsenicals; D016166:Free Radical Scavengers; D010087:Oxides; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D014740:Vidarabine; C024352:fludarabine; D000077237:Arsenic Trioxide