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Experimental Therapeutics, Preclinical Pharmacology |
1 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts; and 2 SCIOS Inc., Sunnyvale, California
Purpose: Transforming growth factors (TGFs) have pleiotropic biological effects on tumor cells and their environment. In multiple myeloma (MM), we have reported that bone marrow stromal cells (BMSCs) from MM patients produce more TGF-ß1 than BMSCs from healthy donors, which in turn induces interleukin (IL)-6 secretion. We show here that the TGF-ß receptor I kinase inhibitor SD-208 significantly decreases secretion of both IL-6 and vascular endothelial growth factor (VEGF) from BMSCs, as well as tumor cell growth triggered by MM cell adhesion to BMSCs.
Experimental Design: Cytokine production and MM cell proliferation triggered by TGF-ß1 or adhesion to BMSCs were examined in the presence or absence of SD-208. Effects of SD-208 on TGF-ß1–induced signaling pathways triggering IL-6 and VEGF transcription in BMSCs were also delineated.
Results: SD-208 significantly inhibits not only transcription but also secretion of both IL-6 and VEGF from BMSCs triggered by either TGF-ß1 or adhesion of MM cells to BMSCs. Moreover, SD-208 decreased tumor cell growth triggered by MM cell adhesion to BMSCs. SD-208 works, at least in part, by blocking TGF-ß1–triggered nuclear accumulation of Smad2/3 and hypoxia-inducible factor 1
, as well as related production of IL-6 and VEGF, respectively.
Conclusions: These studies indicate that SD-208 inhibits production of cytokines mediating MM cell growth, survival, drug resistance, and migration in the BM milieu, thereby providing the preclinical rationale for clinical evaluation of SD-208 to improve patient outcome in MM.
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