Abstract
The Insulin-like growth factor-1 receptor (IGF-1R) is overexpressed in a variety of tumors including breast, prostate and myeloma. Thus, IGF-1R and its downstream signaling effectors are good candidates for molecular-based targeted antitumor therapies. Indeed, protein inhibitors of IGF-1R signaling and IGF-1R blocking antibodies are undergoing clinical trials. Herein, the molecular basis for antibody-mediated IGF-1R signal inhibition has been investigated in a hematopoietic cell line model, FDC-P1, that has been rendered interleukin-3 independent in a ligand-dependent manner through retroviral-mediated expression of IGF-1R (FD/IGF-1R). Furthermore, the ability of an anti-IGF-1R antibody to synergize with signal-transduction pathway inhibitors and induce apoptosis was determined. The alphaIGF-1R antibody, A12, was capable of arresting IGF-1 or insulin-induced FD/IGF-1R cell proliferation in the G1 phase of the cell cycle and resulted in apoptotic induction. A12 effectiveness could be potentiated through combination treatment with small molecule inhibitors of the Ras/Raf/MEK/ERK or PI3K/Akt/mTOR pathways. These results validate the use of the FD/IGF-1R cells to evaluate the effectiveness and mechanisms of targeted IGF-1R therapeutic strategies.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antibody Specificity
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Apoptosis / drug effects
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Apoptosis / physiology
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Cell Division / drug effects
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Cell Division / physiology
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Cell Line, Transformed
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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G1 Phase / drug effects
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G1 Phase / physiology
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Hematopoietic Stem Cells / cytology*
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / enzymology
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Immunotherapy
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Insulin-Like Growth Factor I / pharmacology
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Leukemia / therapy
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, IGF Type 1 / immunology*
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Receptor, IGF Type 1 / metabolism*
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S Phase / drug effects
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S Phase / physiology
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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TOR Serine-Threonine Kinases
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raf Kinases / metabolism
Substances
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Antibodies, Monoclonal
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Enzyme Inhibitors
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Insulin-Like Growth Factor I
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Protein Kinases
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mTOR protein, mouse
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Receptor, IGF Type 1
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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raf Kinases
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases