| Simultaneous inhibition of DNA methyltransferase and histone deacetylase induces p53-independent apoptosis via down-regulation of Mcl-1 in acute myelogenous leukemia cells. | |
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MedLine Citation:
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PMID: 21550660 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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We have recently established the MV4-11 acute myelogenous leukemia (AML) subline, designated as MV4-11 TP53 R248W, which possesses a missense mutation (CGG→TGG; R248W) in the TP53 gene, leading to inactivation of this transcription factor. DNA methyltransferase (DNMT) inhibitor 5-Aza-2'-deoxycytidine (5-AzadC) induced apoptosis in MV4-11, but not in MV4-11 TP53 R248W cells. Another class of anti-epigenetic agent histone deacetylase inhibitor (HDACI) inhibited the proliferation of both MV4-11 and MV4-11 TP53 R248W cells. Notably, when 5-AzadC was combined with HDACI MS-275, apoptosis in MV4-11 TP53 R248W cells was significantly enhanced in parallel with activation of the caspase cascade, up-regulation of p21(waf1) and γ-H2AX, and down-regulation of Mcl-1. Interestingly, inhibition of caspase 3 by the pan-caspase inhibitor attenuated the combination of 5-AzadC and MS-275-mediated apoptosis and down-regulation of Mcl-1 in MV4-11 TP53 R248W cells. Moreover, down-regulation of p21(waf1) in MV4-11 R248W cells by a small interfering RNA blunted activation of caspase 3 after exposure to the combination of 5-AzadC and MS-275, indicating the role of p21(waf1) to activate caspase 3. Taken together, TP53-independent up-regulation of p21(waf1) activates caspase 3 and down-regulates Mcl-1 in AML cells. Combination of 5-AzadC and MS-275 may be a promising treatment strategy for individuals with leukemia in which TP53 is inactivated. |
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Authors:
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Chie Nishioka; Takayuki Ikezoe; Jing Yang; Keiko Udaka; Akihito Yokoyama |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-5-6 |
Journal Detail:
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Title: Leukemia research Volume: - ISSN: 1873-5835 ISO Abbreviation: - Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-5-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7706787 Medline TA: Leuk Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 Elsevier Ltd. All rights reserved. |
Affiliation:
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Department of immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan; The Japanese Society for the Promotion of Science, Chiyoda-ku, Tokyo, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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