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Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions.

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.
AuthorsRoberto R Rosato, Jorge A Almenara, Sarah S Kolla, Sonia C Maggio, Stefanie Coe, Maria S Giménez, Paul Dent, Steven Grant
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 6 Issue 2 Pg. 692-702 (Feb 2007) ISSN: 1535-7163 [Print] United States
PMID17308065 (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.)
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
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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