Bortezomib inhibits the survival and proliferation of bone marrow stromal cells

ABSTRACT

BACKGROUND: Bortezomib is widely used for the treatment of multiple myeloma. Bone marrow stromal cells (BMSCs) endow myeloma cells with survival and growth advantages. However, the influence of bortezomib on BMSCs is not well elucidated. We examined the effects of bortezomib on the survival and growth of BMSCs in vitro. METHODS: The effects of bortezomib on the survival and proliferation of the BMSC MS-5 cell line and on BMSCs obtained from healthy individuals (N=4) and newly diagnosed myeloma patients (N=5) were investigated in vitro. Transmembrane cell migration was evaluated using the Transwell system. A short interfering RNA strategy was used to knock down the expression of chemokine (CXC motif) ligand 12 (CXCL12) mRNA. To examine the effects of bortezomib-exposed BMSCs on the migration and localization of myeloma cells, MS-5 monolayers were treated with bortezomib for 24 hr, washed, and then overlaid with human RPMI8226 myeloma cells. RESULTS: Bortezomib inhibited BMSC proliferation in a concentration-dependent manner, and induced cellular apoptosis. Bortezomib decreased CXCL12 production by BMSCs. Knockdown of CXCL12 mRNA in BMSCs revealed that CXCL12 served as an autocrine growth factor. Short-term bortezomib treatment of BMSC monolayers reduced the tendency of myeloma cells to locate to positions under the monolayers. CONCLUSION: Bortezomib inhibits the survival and growth of BMSCs via downregulation of CXCL12, which may contribute to the clinical effects of this agent.