Abstract
Akt signaling pathway has attracted much attention as a promising target for cancer therapeutics. Herein, we report that Isobavachalcone (IBC), a natural chalcone, potently abrogates Akt signaling and exerts anti-proliferative effects on several human cancer cell lines. Modeling results from the Sybyl/FlexiDock program suggest that IBC potentially binds to the ATP-binding pocket of Akt, which is confirmed by the observations that IBC inhibits Akt1 kinase in vitro. Further studies reveal that IBC significantly abates Akt phosphorylation at Ser-473 and Akt kinase activity in cells, which subsequently leads to inhibition of Akt downstream substrates and evokes significant levels of apoptosis associated with mitochondria pathway.
Copyright 2010 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Caspases / metabolism
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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Cell Nucleus / enzymology
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Cell Survival / drug effects
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Chalcones / chemistry
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Chalcones / metabolism
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Chalcones / pharmacology*
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Cytoplasm / enzymology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Humans
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Male
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Mice
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Mitochondria / drug effects
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Mitochondria / metabolism
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Models, Molecular
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Neoplasms / drug therapy*
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Neoplasms / enzymology
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Neoplasms / metabolism
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Neoplasms / pathology
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / chemistry
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Proto-Oncogene Proteins c-akt / metabolism
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects
Substances
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Chalcones
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Reactive Oxygen Species
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isobavachalcone
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Caspases