Contribution of disruption of the nuclear factor-kappaB pathway to induction of apoptosis in human leukemia cells by histone deacetylase inhibitors and flavopiridol.
Interactions between the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitors (HDACIs) sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) have been examined in human leukemia cells in relation to effects on nuclear factor kappaB (NF-kappaB) activation. Exposure (24 h) of U937 human leukemia cells to NaB (1 mM) or SAHA (1.5 microM) resulted in a marked increase in NF-kappaB DNA binding, effects that were essentially abrogated by coadministration of flavopiridol (100 nM). These events were accompanied by a marked increase in mitochondrial injury, caspase activation, and apoptosis. Mutant cells expressing an IkappaBalpha super-repressor exhibited impairment of NF-kappaB DNA binding in response to HDACIs and a significant although modest increase in apoptosis. However, disruption of the NF-kappaB pathway also increased mitochondrial injury and caspase activation in response to flavopiridol and to an even greater extent to the combination of flavopiridol and HDACIs. Coadministration of flavopiridol with HDACIs down-regulated the X-linked inhibitor of apoptosis (XIAP), Mcl-1, and p21CIP1/WAF1 and activated c-Jun NH2-terminal kinase; moreover, these effects were considerably more pronounced in IkappaBalpha mutants. Similar responses were observed in U937 mutant cells stably expressing RelA/p65 small interfering RNA. In all cases, flavopiridol was significantly more potent than genetic interruption of the NF-kappaB cascade in promoting HDACI-mediated lethality. Together, these findings are consistent with the notion that although inhibition of NF-kappaB activation by flavopiridol contributes to antileukemic interactions with HDACIs, other NF-kappaB-independent flavopiridol actions (e.g., down-regulation of Mcl-1, XIAP, and p21CIP1/WAF1) play particularly critical roles in this phenomenon.
Gao
Ning
N
Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond 23298, USA.
Dai
Yun
Y
Rahmani
Mohamed
M
Dent
Paul
P
Grant
Steven
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002087:Butyrates / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D015536:Down-Regulation; D004347:Drug Interactions; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D020672:I-kappa B Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007938:Leukemia / Q000473:pathology; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051996:Transcription Factor RelA; D020298:U937 Cells; D000077337:Vorinostat; D051636:X-Linked Inhibitor of Apoptosis Protein
D000970:Antineoplastic Agents; D002087:Butyrates; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D020672:I-kappa B Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; D010880:Piperidines; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D000072000:NF-KappaB Inhibitor alpha; C077990:alvocidib; D000077337:Vorinostat; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases