Abstract
Primary glioblastomas (GBMs) commonly overexpress the oncogene epidermal growth factor receptor (EGFR), which leads to increased Ras activity. FTA, a novel Ras inhibitor, produced both time- and dose-dependent caspase-mediated apoptosis in GBM cell lines. EGFR-mediated increase in 3H-thymidine uptake was inhibited by FTA. FACS analysis was performed to determine the percent of apoptotic cells. The sub-Go population of GBM cells was increased from 4.5 to 13.8% (control) to over 45-53.6% in FTA-treated cells within 24 h. Furthermore, FTA also increased the activities of both caspase-3 and -9, and PARP cleavage. Treatment of GBMs with FTA before or after EGF addition to the cultures blocked phosphorylation of Akt and mitogen-activated protein kinases (MAPK). FTA also significantly reduced the amount of EGF-induced Ras-GTP as reflected by a decrease in the level of Ras bound to Raf-RBD-GST. This study demonstrates that inhibition of Ras methylation may provide a therapeutic target for the treatment of GBMs overexpressing EGFR.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis* / drug effects
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Caspase 3
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Caspase 9
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Caspases / metabolism*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Epidermal Growth Factor / pharmacology
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ErbB Receptors / drug effects
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Farnesol / analogs & derivatives*
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Farnesol / pharmacology
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Glioblastoma / enzymology*
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Glioblastoma / pathology
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Humans
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Mitogen-Activated Protein Kinases / metabolism
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Poly(ADP-ribose) Polymerases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Salicylates / pharmacology*
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Signal Transduction / drug effects
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Time Factors
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ras Proteins / antagonists & inhibitors
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ras Proteins / metabolism
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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Salicylates
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farnesylthiosalicylic acid
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Farnesol
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Epidermal Growth Factor
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Poly(ADP-ribose) Polymerases
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ErbB Receptors
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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CASP3 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 9
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Caspases
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ras Proteins