Abstract
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-beta 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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Anti-Inflammatory Agents / pharmacology
-
Apoptosis / drug effects*
-
Apoptosis / physiology
-
Bone Marrow Cells / metabolism
-
Bone Marrow Cells / pathology
-
Cell Line, Tumor
-
Cell Survival / drug effects
-
Cell Survival / genetics
-
Chromosomes, Human / genetics
-
Chromosomes, Human / metabolism
-
Dexamethasone / pharmacology
-
Dose-Response Relationship, Drug
-
Drug Evaluation, Preclinical
-
Drug Resistance, Neoplasm / drug effects
-
Drug Resistance, Neoplasm / genetics
-
Fibroblast Growth Factor 2 / metabolism
-
Humans
-
Indoles / pharmacology*
-
Indoles / therapeutic use*
-
Interleukin-6 / metabolism*
-
MAP Kinase Signaling System / drug effects*
-
Membrane Glycoproteins / metabolism
-
Multiple Myeloma / drug therapy
-
Multiple Myeloma / genetics
-
Multiple Myeloma / metabolism*
-
Multiple Myeloma / pathology
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoinositide-3 Kinase Inhibitors
-
Protein Kinase Inhibitors / pharmacology*
-
Protein Kinase Inhibitors / therapeutic use
-
Proteoglycans / metabolism
-
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
-
Proto-Oncogene Proteins c-akt / metabolism
-
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
-
Receptor Protein-Tyrosine Kinases / genetics
-
Receptor Protein-Tyrosine Kinases / metabolism
-
Stromal Cells / metabolism
-
Stromal Cells / pathology
-
Syndecan-1
-
Syndecans
-
Transforming Growth Factor beta / metabolism
-
Translocation, Genetic / genetics
-
Vascular Endothelial Growth Factor A / metabolism
Substances
-
Anti-Inflammatory Agents
-
BIBF 1000
-
Indoles
-
Interleukin-6
-
Membrane Glycoproteins
-
Phosphoinositide-3 Kinase Inhibitors
-
Protein Kinase Inhibitors
-
Proteoglycans
-
SDC1 protein, human
-
Syndecan-1
-
Syndecans
-
Transforming Growth Factor beta
-
VEGFA protein, human
-
Vascular Endothelial Growth Factor A
-
Fibroblast Growth Factor 2
-
Dexamethasone
-
Receptor Protein-Tyrosine Kinases
-
Proto-Oncogene Proteins c-akt