Abstract
17-Allylamino-17-demethoxygeldanamycin (17-AAG) induces degradation of Hsp90 client proteins, including Bcr-Abl, however, its clinical use as an anti-tumor agent may be limited by toxicity and modest efficacy. We reasoned that Bcr-Abl targeting by RNA interference (RNAi) might selectively increase the activity of 17-AAG against Bcr-Abl+ leukemia cells. 17-AAG in combination with targeting small interfering RNAs (siRNAs) reduced Bcr-Abl protein levels, triggered increases in markers of apoptosis and decreased cell viability more effectively than did control siRNA and 17-AAG together, or Bcr-Abl targeting siRNA alone. Combination targeting strategies such as this may therefore achieve enhanced therapeutic potency.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Benzoquinones / pharmacology*
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Cell Death / drug effects
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Dose-Response Relationship, Drug
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Fusion Proteins, bcr-abl / antagonists & inhibitors
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Fusion Proteins, bcr-abl / genetics*
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Fusion Proteins, bcr-abl / metabolism
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Gene Targeting / methods*
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Humans
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K562 Cells
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Lactams, Macrocyclic / pharmacology*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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RNA Interference*
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RNA, Small Interfering / pharmacology*
Substances
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Benzoquinones
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Lactams, Macrocyclic
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RNA, Small Interfering
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abl-bcr fusion protein, human
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tanespimycin
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Fusion Proteins, bcr-abl