Abstract |
Drug resistance in chronic lymphocytic leukemia (CLL) associated with lesions in the ATM/TP53 pathway represents a major challenge in clinical management. Evidence suggests that heat shock protein-90 (Hsp90) inhibitors may represent a therapeutic option in combination with more conventional therapies. We explored the effects of combining the Hsp90 inhibitor, SNX-7081, with fludarabine in vitro against CLL cells and hematological cell lines. In seven cell lines and 23 patient samples synergy between SNX-7081 and fludarabine (2-FaraA) was apparent in the three TP53 mutated cell lines and at significantly lower concentrations in TP53 or ATM dysfunctional patient cells. In 11/13 2-FaraA-resistant patient samples, SNX-7081 reduced the 50% inhibitory concentration to within a clinically achievable range. Synergy between SNX-7081 and 2-FaraA was evident in both the cell lines and patient samples as a significant decrease in cell viability. Our data suggest that combining SNX-7081 and fludarabine may be effective in the treatment of fludarabine-refractory CLL.
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Authors | O Giles Best, Yiping Che, Nisha Singh, Cecily Forsyth, Richard I Christopherson, Stephen P Mulligan |
Journal | Leukemia & lymphoma
(Leuk Lymphoma)
Vol. 53
Issue 7
Pg. 1367-75
(Jul 2012)
ISSN: 1029-2403 [Electronic] United States |
PMID | 22149137
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- Benzamides
- Cell Cycle Proteins
- DNA-Binding Proteins
- HSP90 Heat-Shock Proteins
- SNX-7081
- Tumor Suppressor Protein p53
- Tumor Suppressor Proteins
- ATM protein, human
- Ataxia Telangiectasia Mutated Proteins
- Protein Serine-Threonine Kinases
- Vidarabine
- fludarabine
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Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Ataxia Telangiectasia Mutated Proteins
- Benzamides
(pharmacology)
- Cell Cycle
(drug effects)
- Cell Cycle Proteins
(genetics, metabolism)
- Cell Line
- Cell Line, Tumor
- Cell Survival
(drug effects)
- DNA-Binding Proteins
(genetics, metabolism)
- Dose-Response Relationship, Drug
- Drug Resistance, Neoplasm
(drug effects)
- Drug Synergism
- Flow Cytometry
- HL-60 Cells
- HSP90 Heat-Shock Proteins
(antagonists & inhibitors)
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell
(genetics, metabolism, pathology)
- Mutation
- Protein Serine-Threonine Kinases
(genetics, metabolism)
- Signal Transduction
(drug effects)
- Tumor Cells, Cultured
- Tumor Suppressor Protein p53
(genetics, metabolism)
- Tumor Suppressor Proteins
(genetics, metabolism)
- Vidarabine
(analogs & derivatives, pharmacology)
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