Abstract
The PI3 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of PI3 kinase, we screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family. Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block PI3 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both PI3 kinase alpha and mTOR. PI-103 showed significant activity in xenografted tumors with no observable toxicity. These data demonstrate an emergent efficacy due to combinatorial inhibition of mTOR and PI3 kinase alpha in malignant glioma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Class I Phosphatidylinositol 3-Kinases
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Enzyme Activation
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ErbB Receptors / metabolism
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Glioma / drug therapy*
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Glioma / enzymology*
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Glioma / pathology
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Humans
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Mice
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Mice, Inbred BALB C
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Organoplatinum Compounds / pharmacology
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Isoforms / antagonists & inhibitors
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Protein Kinases / metabolism*
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Signal Transduction
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Substrate Specificity
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TOR Serine-Threonine Kinases
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Treatment Outcome
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Tumor Suppressor Protein p53 / metabolism
Substances
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Organoplatinum Compounds
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Phosphoinositide-3 Kinase Inhibitors
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Protein Isoforms
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Tumor Suppressor Protein p53
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platinum 103
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Class I Phosphatidylinositol 3-Kinases
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PIK3CB protein, human
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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PTEN Phosphohydrolase