Targeting receptor kinases by a novel indolinone derivative in multiple myeloma: abrogation of stroma-derived interleukin-6 secretion and induction of apoptosis in cytogenetically defined subgroups
| Autor: | Carsten Müller-Tidow, Doris Wenning, Rolf M. Mesters, Guido Bisping, Wolfgang E. Berdel, Joelle Tchinda, Matthias Stelljes, Hubert Serve, Frank Hilberg, Martin Kropff, Joachim Kienast, Christian Scheffold, Martin Stefanic, Sergey Bessonov, Britta Dreyer, Gerald Juergen Roth, Peter Liebisch, Gerd Munzert, Nicola Lang |
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| Rok vydání: | 2005 |
| Předmět: |
MAPK/ERK pathway
Vascular Endothelial Growth Factor A Indoles Syndecans Cell Survival MAP Kinase Signaling System Immunology Cell Basic fibroblast growth factor Anti-Inflammatory Agents Drug Evaluation Preclinical Apoptosis Bone Marrow Cells Biology Fibroblast growth factor Biochemistry Dexamethasone Translocation Genetic chemistry.chemical_compound Phosphatidylinositol 3-Kinases Transforming Growth Factor beta Cell Line Tumor medicine Chromosomes Human Humans Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Phosphoinositide-3 Kinase Inhibitors Membrane Glycoproteins Dose-Response Relationship Drug Kinase Interleukin-6 Receptor Protein-Tyrosine Kinases Cell Biology Hematology Molecular biology medicine.anatomical_structure chemistry Cell culture Drug Resistance Neoplasm Fibroblast Growth Factor 2 Proteoglycans Syndecan-1 Stromal Cells Multiple Myeloma Proto-Oncogene Proteins c-akt |
| Zdroj: | Blood. 107(5) |
| ISSN: | 0006-4971 |
| Popis: | In multiple myeloma (MM), both vascular endothelial (VEGF) and basic fibroblast growth factor (bFGF) promote tumor growth and survival. We have used the novel indolinone BIBF 1000 to study effects of simultaneous inhibition of VEGF, FGF and transforming growth factor-β on MM cells and their interactions with bone marrow stroma cells (BMSCs). Both, in the absence and presence of myeloma-stroma cell contacts, BIBF 1000 abrogated BMSC-derived secretion of interleukin-6 (IL-6). In addition, BIBF 1000 directly induced apoptosis in t(4;14)–positive cell lines as well as in CD138+ marrow cells from patients with t(4;14) myeloma. To a similar extent, BIBF 1000 induced apoptosis in MM.1S and MM.1R cells carrying the translocation t(14;16). In case of MM.1S and other dexamethasone-sensitive t(14;16) cell lines, BIBF 1000 and dexamethasone had additive proapoptotic effects. Induction of apoptosis by BIBF 1000 was associated with inhibition of the mitogen-activated protein kinases (MAPK) pathway in t(4;14) and inhibition of the phosphatidyl-inositol-3 kinase/AKT pathway in t(14;16) cells. Apoptotic effects did not occur in t(4;14)–or t(14;16)–positive MM cells carrying n- or k-Ras mutations. The data provide the rationale for clinical evaluation of this class of targeted kinase inhibitors in MM with focus on defined cytogenetic subgroups. |
| Databáze: | OpenAIRE |
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