| Abstract | OBJECTIVE: Heat shock protein 90 (HSP90) chaperones and maintains the molecular integrity of a variety of signal transduction proteins, including the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogenic protein, a genetic abnormality that is frequently observed in anaplastic large cell lymphoma (ALCL) cells. Here we demonstrate that HSP90 is overexpressed in primary and cultured ALK-positive and ALK-negative ALCL cells, and we evaluate the potential role of the small molecule inhibitor of HSP90, 17-allylamino-17-demethoxygeldanamycin (17-AAG) in treating ALCL. METHODS: The antiproliferative effect of 17-AAG-cultured cells was determined by MTS assay. Apoptosis and cell-cycle arrest were determined by Annexin-V/propidium iodide and propidium iodide staining, respectively, and fluorescein-activated cell sorting analysis. Expression of HSP90 was evaluated by immunohistochemistry, and molecular changes were determined by Western blot. RESULTS: Treatment of cultured ALCL cells with 17-AAG induced cell-cycle arrest and apoptosis, irrespective of ALK expression. At the molecular level, 17-AAG induced degradation of ALK and Akt proteins, dephosphorylated extracellular signal-regulated kinase, and degraded the cell-cycle regulatory protein cyclin D1 and its cyclin-dependent kinases, CDK4 and CDK6, but had a differential effect on p27 and p53 proteins. Inhibition of extracellular signal-regulated kinase phosphorylation by the mitogen activated protein kinase inhibitor U0126 induced cell death in all ALCL cell lines, and sublethal concentration 17-AAG showed synergistic antiproliferative effects when combined with U0126 or doxorubicin. CONCLUSION: Our data demonstrate that targeting HSP90 function by 17-AAG may offer a novel therapeutic strategy for ALCL, either as single-agent activity or by combining 17-AAG with conventional or targeted therapeutic schemes. |
| Authors | Georgios V Georgakis, Yang Li, Georgios Z Rassidakis, L Jeffrey Medeiros, Anas Younes
(Affiliation: Departments of Lymphoma and Myeloma, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA.)
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| Journal | Experimental hematology
(Exp Hematol)
Vol. 34
Issue 12
Pg. 1670-9
(Dec 2006)
ISSN: 0301-472X Netherlands |
| PMID | 17157164
(Publication Type: Journal Article)
|
| Chemical References |
- 17-(allylamino)-17-demethoxygeldanamycin
- Benzoquinones
- Butadienes
- Cyclins
- HSP90 Heat-Shock Proteins
- Lactams, Macrocyclic
- Nitriles
- U 0126
- cyclin D
- Doxorubicin
- anaplastic lymphoma kinase
- Protein-Tyrosine Kinases
- CDK4 protein, human
- CDK6 protein, human
- Cyclin-Dependent Kinase 4
- Cyclin-Dependent Kinase 6
- Extracellular Signal-Regulated MAP Kinases
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
- Caspase 3
|
| Topics |
- Apoptosis
(drug effects)
- Benzoquinones
(pharmacology)
- Butadienes
(pharmacology)
- Caspase 3
(drug effects, metabolism)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cyclin-Dependent Kinase 4
(drug effects, metabolism)
- Cyclin-Dependent Kinase 6
(drug effects, metabolism)
- Cyclins
(drug effects, metabolism)
- Dose-Response Relationship, Drug
- Down-Regulation
(drug effects)
- Doxorubicin
(pharmacology)
- Drug Synergism
- Extracellular Signal-Regulated MAP Kinases
(drug effects, metabolism)
- G0 Phase
(drug effects)
- G1 Phase
(drug effects)
- HSP90 Heat-Shock Proteins
(antagonists & inhibitors, biosynthesis)
- Humans
- Lactams, Macrocyclic
(pharmacology)
- Lymphoma, Large-Cell, Anaplastic
(metabolism)
- Mitogen-Activated Protein Kinase 1
(drug effects, metabolism)
- Mitogen-Activated Protein Kinase 3
(drug effects, metabolism)
- Nitriles
(pharmacology)
- Phosphorylation
- Protein-Tyrosine Kinases
(biosynthesis, drug effects)
- Time Factors
|
