Abstract
Hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in the world. The aim of the present study is to determine the antitumor effect of PF-04691502, a potent inhibitor of PI3K and mTOR kinases, on the apoptosis and angiogenesis of the hepatoma cancer cells. Our results indicate that treatment of cancer cells with PF-04691502 reduces cell viability and inhibits cell growth in a dose-dependent manner. PF-04691502 triggers apoptosis via a mitochondrial pathway, accompanied by activation of caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP). Pre-treatment of hepatoma cells with the caspase-3 inhibitor (z-DEVD-fmk) blocks the PF-04691502-induced death of these cells. In addition, growth factors-induced tube formation and the migration of HUVECs are markedly inhibited by PF-04691502 treatment. The mechanisms of anti-angiogenesis of PF-04691502 are associated with inhibiting the expression of VEGF and HIF-1α. Based on the overall results, we suggest that PF-04691502 reduces hepatocellular carcinoma cell viability, induces cell apoptosis, and inhibits cell growth and tumor angiogenesis, implicating its potential therapeutic value in the treatment of HCC.
Copyright © 2013 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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Apoptosis / drug effects*
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Carcinoma, Hepatocellular / blood supply
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Carcinoma, Hepatocellular / drug therapy*
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Carcinoma, Hepatocellular / pathology
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Caspases / metabolism
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Cell Growth Processes / drug effects
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Cell Movement / drug effects
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Enzyme Activation / drug effects
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G1 Phase Cell Cycle Checkpoints / drug effects*
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Hep G2 Cells
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Human Umbilical Vein Endothelial Cells / drug effects
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
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Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis
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Liver Neoplasms / blood supply
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Liver Neoplasms / drug therapy*
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Liver Neoplasms / pathology
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Neovascularization, Pathologic / drug therapy
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Neovascularization, Pathologic / pathology
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PTEN Phosphohydrolase / antagonists & inhibitors
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PTEN Phosphohydrolase / biosynthesis
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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 / metabolism
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Pyridones / pharmacology*
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Pyrimidines / pharmacology*
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / biosynthesis
Substances
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2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Pyridones
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Pyrimidines
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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PTEN protein, human
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Caspases