title: Simultaneous inhibition of DNA methyltransferase and histone deacetylase induces p53-independent apoptosis via down-regulation of Mcl-1 in acute myelogenous leukemia cells.
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.
authors.affiliation: Department of immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Keiko
authors.initials: K
authors.lastname: Udaka
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057890:Epigenomics; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020125:Mutation, Missense / Q000235:genetics; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C118739:entinostat; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine