Arsenic trioxide induces apoptosis preferentially in B-CLL cells of patients with unfavourable prognostic factors including del17p13
| Autor: | Christoph Heyder, Zlatko Trajanoski, Richard Greil, Daniela Asslaber, Christine Papak, Olaf Merkel, Claudia Holler, Inge Tinhofer, Andreas Prokesch, Markus Stöcher, Frank Hamacher, Marcel Scheideler |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Programmed cell death Chronic lymphocytic leukemia Lymphocyte Apoptosis Arsenicals chemistry.chemical_compound Arsenic Trioxide immune system diseases hemic and lymphatic diseases Drug Discovery Humans Medicine Arsenic trioxide Genetics (clinical) chemistry.chemical_classification Reactive oxygen species Superoxide Dismutase business.industry Oxides Free Radical Scavengers Prognosis medicine.disease Leukemia Lymphocytic Chronic B-Cell Molecular medicine Fludarabine Enzyme Activation Oxidative Stress medicine.anatomical_structure chemistry Drug Resistance Neoplasm Caspases Immunology Molecular Medicine Female Chromosome Deletion Poly(ADP-ribose) Polymerases Reactive Oxygen Species business Vidarabine Chromosomes Human Pair 17 medicine.drug |
| Zdroj: | Journal of Molecular Medicine. 86:541-552 |
| ISSN: | 1432-1440 0946-2716 |
| DOI: | 10.1007/s00109-008-0314-6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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