| Use of a novel histone deacetylase inhibitor to induce apoptosis in cell lines of acute lymphoblastic leukemia. | |
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MedLine Citation:
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PMID: 15075075 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND OBJECTIVES: Chromatin structure and thereby transcription is controlled by the level of acetylation of histones, which is determined by the balance between histone acetyl transferase (HAT) activity and histone deacetylase (HDAC) activity. HDAC inhibitors are a class of compounds able to regulate gene expression by modulating chromatin structure. There are two major classes of HDAC inhibitors: the hydroxamic acid derivatives such as trichostatin A (TSA) or SAHA, and the butyrates such as phenyl-butyrate. HDAC inhibitors interfere with differentiation, proliferation and apoptosis in tumor cells. Here, we investigated the activity of a new hydroxamic acid derivative, LAQ824, on lymphoblastic cells. DESIGN AND METHODS: Four different pre-B lymphoblastic cell lines: Sup-B15 and TMD-5, both t(9;22) positive, SEM, t(4;11) positive, and NALM-6 cells were exposed to the hydroxamic acid derivatives, LAQ824 and TSA. Histone hyperacetylation, apoptosis, cell cycle and related pathways were assessed by flow cytometry and Western blotting. RESULTS: LAQ824 significantly inhibited the proliferation of leukemic lymphoblastic cell lines. The effect of LAQ824 was due to increased apoptosis accompanied by activation of caspase-3 and caspase-9, cleavage of poly(ADP-ribose)-polymerase (PARP) as well as by down-regulation of Bcl-2 and disruption of the mitochondrial membrane potential. Surprisingly, LAQ824-induced apoptosis was at least partially independent of caspase activation as indicated by the fact that LAQ824-induced apoptosis was inhibited only partially in both t(9;22) positive Sup-B15 and TMD-5 cells, whereas no inhibition was observed in t(4;11) positive SEM cells upon exposure to the polycaspase inhibitor zVAD-fmk. INTERPRETATION AND CONCLUSIONS: Our study establishes that LAQ824 is a promising agent for the therapy of acute lymphoblastic leukemia. |
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Authors:
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Annette Romanski; Biserka Bacic; Gesine Bug; Heike Pfeifer; Hilal Gul; Stacy Remiszewski; Dieter Hoelzer; Peter Atadja; Martin Ruthardt; Oliver G Ottmann |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Haematologica Volume: 89 ISSN: 1592-8721 ISO Abbreviation: Haematologica Publication Date: 2004 Apr |
Date Detail:
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Created Date: 2004-04-12 Completed Date: 2006-02-27 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0417435 Medline TA: Haematologica Country: Italy |
Other Details:
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Languages: eng Pagination: 419-26 Citation Subset: IM |
Affiliation:
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Med. Klinik III/Abtl. Hämatologie, Johann Wolfgang Goethe-Universität, 60590 Frankfurt, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects* Burkitt Lymphoma / drug therapy, genetics, pathology* Cell Line, Tumor Enzyme Inhibitors / pharmacology* Histone Deacetylase Inhibitors* Humans Hydroxamic Acids / pharmacology Translocation, Genetic |
| Chemical | |
Reg. No./Substance:
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0/Enzyme Inhibitors; 0/Histone Deacetylase Inhibitors; 0/Hydroxamic Acids; 0/LAQ824; 58880-19-6/trichostatin A |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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