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.
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.
Bisping
Guido
G
Department of Medicine/Hematology and Oncology, University of Muenster, Albert-Schweitzer-Str. 33, D-48129 Muenster, Germany.
Kropff
Martin
M
Wenning
Doris
D
Dreyer
Britta
B
Bessonov
Sergey
S
Hilberg
Frank
F
Roth
Gerald J
GJ
Munzert
Gerd
G
Stefanic
Martin
M
Stelljes
Matthias
M
Scheffold
Christian
C
Müller-Tidow
Carsten
C
Liebisch
Peter
P
Lang
Nicola
N
Tchinda
Jöelle
J
Serve
Hubert L
HL
Mesters
Rolf M
RM
Berdel
Wolfgang E
WE
Kienast
Joachim
J
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011509:Proteoglycans / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D053668:Syndecan-1; D053667:Syndecans; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D016222:Fibroblast Growth Factor 2; D007211:Indoles; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases; D053668:Syndecan-1; D053667:Syndecans; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C509119:BIBF 1000; C508241:SDC1 protein, human; C467484:VEGFA protein, human