Abstract
Here we report an oral alkylphospholipid perifosine dramatically sensitizes chemo-resistant ovarian cancer cells to paclitaxel induced cell death and apoptosis in vitro. We found that co-administration perifosine with paclitaxel in human ovarian cancer cells led to the inhibition of AKT/mTOR complex 1 (mTORC1), a marked increase in ceramide and reactive oxygen species (ROS) production, and a striking increase in the activation of pro-apoptosis pathways, including caspase 3, c-Jun N-terminal kinases (JNK) and AMP-activated protein kinase (AMPK). These signaling events together caused a marked increase of cancer cell apoptosis. Combining paclitaxel with perifosine may represent a novel anti-ovarian cancer strategy.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / drug effects*
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Blotting, Western
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Caspase 3 / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Ceramides / metabolism
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Drug Synergism
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Female
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HT29 Cells
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Paclitaxel / pharmacology*
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Phosphorylcholine / analogs & derivatives*
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Phosphorylcholine / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Reactive Oxygen Species / metabolism
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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Ceramides
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Reactive Oxygen Species
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Phosphorylcholine
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perifosine
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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JNK Mitogen-Activated Protein Kinases
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AMP-Activated Protein Kinases
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PRKAA1 protein, human
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Caspase 3
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Paclitaxel