Abstract
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 p21waf1 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 p21waf1 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 p21waf1 to activate caspase 3. Taken together, TP53-independent up-regulation of p21waf1 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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Azacitidine / analogs & derivatives*
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Azacitidine / pharmacology
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Benzamides / pharmacology*
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Blotting, Western
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Cell Cycle / drug effects
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Cell Proliferation / drug effects
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Cyclin-Dependent Kinase Inhibitor p21 / antagonists & inhibitors
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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DNA Modification Methylases / antagonists & inhibitors
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Decitabine
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Drug Therapy, Combination
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Enzyme Inhibitors / pharmacology
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Epigenomics
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Flow Cytometry
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Gene Expression Regulation, Neoplastic / drug effects*
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism
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Leukemia, Myeloid, Acute / pathology*
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Mutation, Missense / genetics
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Myeloid Cell Leukemia Sequence 1 Protein
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyridines / pharmacology*
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RNA, Messenger / genetics
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RNA, Small Interfering / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / genetics*
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Tumor Suppressor Protein p53 / metabolism
Substances
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Benzamides
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Enzyme Inhibitors
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Histone Deacetylase Inhibitors
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Myeloid Cell Leukemia Sequence 1 Protein
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Proto-Oncogene Proteins c-bcl-2
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Pyridines
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RNA, Messenger
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RNA, Small Interfering
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TP53 protein, human
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Tumor Suppressor Protein p53
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entinostat
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Decitabine
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DNA Modification Methylases
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Azacitidine