Abstract
SNX-2112, a novel inhibitor of Hsp90 currently used as an anti-tumor drug, induces apoptosis in multiple tumor cell lines. It destabilizes specific client proteins, but the molecular mechanism of the apoptosis effect of SNX-2112 is poorly understood. Here, we analyzed the apoptotic effect of SNX-2112 on human chronic myeloid leukemia (CML) K562 cells. Transcriptomic and proteomic approaches further revealed that caspase signals originated from mitochondria dysfunction, mediated by Akt signaling pathway inactivity. Additionally, SNX-2112 prolonged the survival time of NOD/SCID mice inoculated with K562 tumor cells. Our results demonstrated the therapeutic potential of SNX-2112 against human CML.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Apoptosis / genetics
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Apoptosis / physiology
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Gene Expression Profiling
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HSP90 Heat-Shock Proteins / antagonists & inhibitors
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Humans
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K562 Cells
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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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Membrane Potential, Mitochondrial / drug effects
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neoplasm Transplantation
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Proteomics
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Signal Transduction / drug effects
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Transplantation, Heterologous
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bcl-Associated Death Protein / metabolism
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bcl-X Protein / metabolism
Substances
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Antineoplastic Agents
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BAD protein, human
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BCL2L1 protein, human
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HSP90 Heat-Shock Proteins
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Heterocyclic Compounds, 4 or More Rings
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Mitochondrial Proteins
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Neoplasm Proteins
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SNX 2112
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bcl-Associated Death Protein
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bcl-X Protein