Abstract |
The mechanism and functional significance of XIAP and Mcl-1 down-regulation in human leukemia cells exposed to the histone deacetylase inhibitor vorinostat and the cyclin-dependent kinase inhibitor flavopiridol was investigated. Combined exposure of U937 leukemia cells to marginally toxic concentrations of vorinostat and flavopiridol resulted in a marked increase in mitochondrial damage and apoptosis accompanied by pronounced reductions in XIAP and Mcl-1 mRNA and protein. Down-regulation of Mcl-1 and XIAP expression by vorinostat/ flavopiridol was associated with enhanced inhibition of phosphorylation of RNA polymerase II and was amplified by caspase-mediated protein degradation. Chromatin immunoprecipitation analysis revealed that XIAP and Mcl-1 down-regulation were also accompanied by both decreased association of nuclear factor-kappaB (XIAP) and increased E2F1 association (Mcl-1) with their promoter regions, respectively. Ectopic expression of Mcl-1 but not XIAP partially protected cells from flavopiridol/ vorinostat-mediated mitochondrial injury at 48 h, but both did not significantly restored clonogenic potential. Flavopiridol/ vorinostat-mediated transcriptional repression of XIAP, Mcl-1-enhanced apoptosis, and loss of clonogenic potential also occurred in primary acute myelogenous leukemia (AML) blasts. Together, these findings indicate that transcriptional repression of XIAP and Mcl-1 by flavopiridol/ vorinostat contributes functionally to apoptosis induction at early exposure intervals and raise the possibility that expression levels may be a useful surrogate marker for activity in current trials.
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Authors | Roberto R Rosato, Jorge A Almenara, Sarah S Kolla, Sonia C Maggio, Stefanie Coe, Maria S Giménez, Paul Dent, Steven Grant |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 6
Issue 2
Pg. 692-702
(Feb 2007)
ISSN: 1535-7163 [Print] United States |
PMID | 17308065
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- AIFM1 protein, human
- Antineoplastic Agents
- Apoptosis Inducing Factor
- Butyrates
- Flavonoids
- Histone Deacetylase Inhibitors
- Hydroxamic Acids
- Myeloid Cell Leukemia Sequence 1 Protein
- Neoplasm Proteins
- Piperidines
- Proto-Oncogene Proteins c-bcl-2
- RNA, Messenger
- X-Linked Inhibitor of Apoptosis Protein
- XIAP protein, human
- alvocidib
- Vorinostat
- Cytochromes c
- Cyclin-Dependent Kinases
- Caspases
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Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Apoptosis Inducing Factor
(metabolism)
- Blast Crisis
- Blotting, Western
- Butyrates
(pharmacology)
- Caspases
(metabolism)
- Chromatin Immunoprecipitation
- Cyclin-Dependent Kinases
(antagonists & inhibitors)
- Cytochromes c
(metabolism)
- Down-Regulation
- Drug Interactions
- Flavonoids
(pharmacology)
- Histone Deacetylase Inhibitors
- Humans
- Hydroxamic Acids
(pharmacology)
- Leukemia, Myeloid, Acute
(drug therapy, metabolism)
- Membrane Potential, Mitochondrial
(drug effects)
- Myeloid Cell Leukemia Sequence 1 Protein
- Neoplasm Proteins
(antagonists & inhibitors, metabolism)
- Piperidines
(pharmacology)
- Proto-Oncogene Proteins c-bcl-2
(antagonists & inhibitors, metabolism)
- RNA, Messenger
(genetics, metabolism)
- Reverse Transcriptase Polymerase Chain Reaction
- Transcription, Genetic
(drug effects)
- Tumor Stem Cell Assay
- U937 Cells
(drug effects)
- Vorinostat
- X-Linked Inhibitor of Apoptosis Protein
(antagonists & inhibitors, genetics, metabolism)
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