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Blood, 1 March 2006, Vol. 107, No. 5, pp. 2079-2089.
Prepublished online as a Blood First Edition Paper on November 8, 2005; DOI 10.1182/blood-2004-11-4250.
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Submitted November 5, 2004
Accepted October 21, 2005
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
Guido Bisping, Martin Kropff, Doris Wenning, Britta Dreyer, Sergey Bessonov, Frank Hilberg, Gerald J Roth, Gerd Munzert, Martin Stefanic, Matthias Stelljes, Christian Scheffold, Carsten Muller-Tidow, Peter Liebisch, Nicola Lang, Joelle Tchinda, Hubert L Serve, Rolf M Mesters, Wolfgang E Berdel, and Joachim Kienast*
Department of Medicine / Hematology and Oncology, University of Muenster, Muenster, Germany
Boehringer Ingelheim Austria GmbH, Vienna, Austria
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
Department of Medicine III, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany
Institute of Human Genetics, University of Muenster, Muenster, Germany
* Corresponding author; email: kienast{at}uni-muenster.de.
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- 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.
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