Abstract |
Interactions between the histone deacetylase ( HDAC) inhibitors suberanoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino 17-demethoxygeldanamycin (17-AAG) have been examined in Bcr-Abl(+) human leukemia cells (K562 and LAMA84), including those sensitive and resistant to STI571 ( imatinib mesylate). Cotreatment with 17-AAG and SAHA or SB synergistically induced mitochondrial dysfunction ( cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and growth inhibition. Similar effects were observed in LAMA84 cells and K562 cells resistant to STI571, as well as in CD34(+) cells isolated from the bone marrows of three patients with chronic myelogenous leukemia. These events were associated with increased binding of Bcr-Abl, Raf-1, and Akt to Hsp70, and inactivation of extracellular signal-regulated kinase 1/2 and Akt. In addition, 17-AAG/SAHA abrogated the DNA binding and the transcriptional activities of signal transducer and activator of transcription (STAT) 5 in K562 cells, including those ectopically expressing a constitutively active STAT5A construct. Cotreatment with 17-AAG and SAHA also induced down-regulation of Mcl-1, Bcl-xL, and B-Raf; up-regulation of Bak; cleavage of 14-3-3 proteins; and a profound conformational change in Bax accompanied by translocation to the membrane fraction. Moreover, ectopic expression of Bcl-2 attenuated cell death induced by this regimen, implicating mitochondrial injury in the lethality observed. Together, these findings raise the possibility that combining HDAC inhibitors with the Hsp90 antagonist 17-AAG may represent a novel strategy against Bcr-Abl(+) leukemias, including those resistant to STI571.
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Authors | Mohamed Rahmani, Erin Reese, Yun Dai, Cheryl Bauer, Lora B Kramer, Mei Huang, Richard Jove, Paul Dent, Steven Grant |
Journal | Molecular pharmacology
(Mol Pharmacol)
Vol. 67
Issue 4
Pg. 1166-76
(Apr 2005)
ISSN: 0026-895X [Print] United States |
PMID | 15625278
(Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- BAX protein, human
- Benzamides
- Benzoquinones
- DNA-Binding Proteins
- Enzyme Inhibitors
- Histone Deacetylase Inhibitors
- Hydroxamic Acids
- Lactams, Macrocyclic
- Milk Proteins
- Piperazines
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins c-bcl-2
- Pyrimidines
- STAT5 Transcription Factor
- STAT5A protein, human
- Trans-Activators
- Tumor Suppressor Proteins
- bcl-2-Associated X Protein
- Rifabutin
- tanespimycin
- Vorinostat
- Imatinib Mesylate
- DNA
- Fusion Proteins, bcr-abl
- AKT1 protein, human
- Protein Serine-Threonine Kinases
- Proto-Oncogene Proteins c-akt
- raf Kinases
- MAP Kinase Kinase Kinases
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Topics |
- Apoptosis
(drug effects)
- Benzamides
- Benzoquinones
- DNA
(metabolism)
- DNA-Binding Proteins
(metabolism)
- Down-Regulation
- Drug Synergism
- Enzyme Inhibitors
(pharmacology)
- Fusion Proteins, bcr-abl
(analysis)
- Histone Deacetylase Inhibitors
- Humans
- Hydroxamic Acids
(pharmacology)
- Imatinib Mesylate
- K562 Cells
- Lactams, Macrocyclic
- MAP Kinase Kinase Kinases
(physiology)
- Milk Proteins
(metabolism)
- Mitochondria
(drug effects)
- Piperazines
(pharmacology)
- Protein Conformation
- Protein Serine-Threonine Kinases
(physiology)
- Protein Transport
(drug effects)
- Proto-Oncogene Proteins
(physiology)
- Proto-Oncogene Proteins c-akt
- Proto-Oncogene Proteins c-bcl-2
(chemistry)
- Pyrimidines
(pharmacology)
- Rifabutin
(analogs & derivatives, pharmacology)
- STAT5 Transcription Factor
- Trans-Activators
(metabolism)
- Transcription, Genetic
(drug effects)
- Tumor Suppressor Proteins
- Vorinostat
- bcl-2-Associated X Protein
- raf Kinases
(physiology)
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