Abstract
SNX-2112 is a heat shock protein 90 (Hsp90) inhibitor with anticancer properties currently in clinical trials. This study investigated the effects of SNX-2112 on inhibition of cell growth, the cell cycle, and apoptosis in MCF-7 human breast cancer cells, in addition to the various molecular mechanisms. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis suggest that SNX-2112 inhibits cell growth in a time- and dose-dependent manner more potently than 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), a traditional Hsp90 inhibitor, probably as a result of cell-cycle arrest at the G2/M phase and the induction of apoptosis. Downregulation of Bcl-2 and Bcl-xL, upregulation of Bax, cleavage of caspase-9 and poly (ADP-ribose) polymerase (PARP), and degradation of the breast cancer-related Hsp90 client proteins human epidermal growth factor receptor-2 (HER2), Akt, Raf-1, and nuclear factor kappa-B kinase (IKK) were observed in SNX-2112 treated cells by Western blot assay. These findings suggest that the molecular mechanisms of cell-growth inhibition by SNX-2112 involve activation of the mitochondrial apoptotic pathway and the degradation of breast cancer-related proteins.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects*
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Benzoquinones / pharmacology
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Blotting, Western
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Caspase 9 / genetics
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Caspase 9 / metabolism
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Cell Cycle Checkpoints / drug effects*
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Cell Cycle Checkpoints / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Female
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Gene Expression Regulation, Neoplastic / drug effects*
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Humans
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Lactams, Macrocyclic / pharmacology
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Mitochondria / drug effects*
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Mitochondria / genetics
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Mitochondria / metabolism
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Poly(ADP-ribose) Polymerases / genetics
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / metabolism
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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Antineoplastic Agents
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Benzoquinones
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HSP90 Heat-Shock Proteins
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Heterocyclic Compounds, 4 or More Rings
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Lactams, Macrocyclic
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SNX 2112
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bcl-2-Associated X Protein
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bcl-X Protein
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tanespimycin
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Poly(ADP-ribose) Polymerases
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Receptor, ErbB-2
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-raf
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Caspase 9