The IL-6 receptor antagonist SANT-7 overcomes bone marrow stromal cell-mediated drug resistance of multiple myeloma cells.
The bone marrow micro-environment produces a number of different survival factors that are important for the malignant growth and drug resistance of multiple myeloma (MM) cells. One of the main factors reported to be essential for survival and growth of MM cells in some experimental systems is IL-6. Therefore, the development and testing of substances that interfere with IL-6 or IL-6 receptor (IL-6R) function might have therapeutic value for the treatment of MM. We analyzed the effect of the IL-6R antagonist SANT-7 on growth and survival of the IL-6--dependent MM cell lines INA-6 and XG-1 as well as primary MM cells from 7 patients co-cultured with bone marrow stromal cells (BMSCs). In particular, we were interested in whether SANT-7 enhances the growth-inhibitory effects of dexamethasone (Dex) and all-trans-retinoic acid (ATRA). None of the drugs when tested as a single substance, including SANT-7, induced major growth inhibition if MM cells were co-cultured with primary human BMSCs. However, when Dex and ATRA were given in combination with SANT-7, strong growth inhibition was achieved in cell lines and primary MM cells. This effect was due to cell-cycle arrest and induction of apoptosis.
Hönemann
D
D
Department of Hematology, Oncology and Tumor Immunology, Humboldt University of Berlin, University Medical Center Charité, Robert-Rössle-Klinik, Berlin, Germany.
Chatterjee
M
M
Savino
R
R
Bommert
K
K
Burger
R
R
Gramatzki
M
M
Dörken
B
B
Bargou
R C
RC
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D005455:Fluorescent Antibody Technique; D006801:Humans; D015850:Interleukin-6 / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017154:Stromal Cells / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; C432252:SANT-7; D014212:Tretinoin; D003907:Dexamethasone