Synergy between an IGF-1R antibody and Raf/MEK/ERK and PI3K/Akt/mTOR pathway inhibitors in suppressing IGF-1R-mediated growth in hematopoietic cells
| Autor: | Linda S. Steelman, Fred E. Bertrand, Edmond R. White, Dale L. Ludwig, William H. Chappell, John G. Shelton, Steve L. Abrams, James A. McCubrey |
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| Rok vydání: | 2006 |
| Předmět: |
MAPK/ERK pathway
Cancer Research medicine.medical_treatment Apoptosis Receptor IGF Type 1 S Phase Mice Phosphatidylinositol 3-Kinases Antibody Specificity Blocking antibody medicine Animals Enzyme Inhibitors Insulin-Like Growth Factor I Extracellular Signal-Regulated MAP Kinases Protein kinase B PI3K/AKT/mTOR pathway Cell Line Transformed Leukemia biology Cell growth TOR Serine-Threonine Kinases G1 Phase Antibodies Monoclonal Hematology Cell cycle Hematopoietic Stem Cells Cytokine Oncology Mitogen-activated protein kinase biology.protein Cancer research raf Kinases Immunotherapy Mitogen-Activated Protein Kinases Protein Kinases Proto-Oncogene Proteins c-akt Cell Division Signal Transduction |
| Zdroj: | Leukemia. 20:1254-1260 |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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