ABSTRACT
We examined the effect of thalidomide and dexamethasone on the migration of multiple myeloma (MM) cell lines, U266, RPMI8226, and NCI-H929, using chemotaxis chamber plates. U266 underwent chemotactic migration in response to stromal-cell derived factor-1 alpha (SDF-1alpha), and other cell lines underwent random migration in response to SDF-1alpha or monocyte chemotactic protein-1 alpha. Following preincubation with 1 mug/ml thalidomide, the cell lines showed reduced migratory capacity in response to SDF-1alpha. Concerning the corresponding receptors, CXC chemokine receptor 4 was detected only on the surface of U266, by flow cytometry, whereas chemokine (C-C motif) receptor 2 was not detected on all three cell lines. Moreover, decreased migration by thalidomide was not accompanied by altered expression of the corresponding receptors of each cell line. This is the first report to show the effects of thalidomide on the migration of MM cell lines. The results suggest that the inhibition of chemotactic migration might be one of the mechanisms of the success of thalidomide in controlling MM.
Subject(s)
Antineoplastic Agents/pharmacology , Chemotaxis/drug effects , Plasma Cells/drug effects , Thalidomide/pharmacology , Cell Line , Chemokine CXCL12/drug effects , Humans , Multiple Myeloma/drug therapy , Receptors, Chemokine/drug effectsABSTRACT
BACKGROUND: The molecular mechanism of natural killer (NK) cell cytotoxicity to myeloma cells remains unclear. We investigated whether MHC class I-related chain (MIC), a ligand of NKG2D that is an activating NK cell receptor, is involved in the cytotoxicity of NK cells toward myeloma cells, and examined the effects of various drugs on the cytotoxicity. METHODS: Two human myeloma cell lines and fresh myeloma cells from 10 patients were used. MIC expression was examined by flow cytometry and reverse transcription (RT)-PCR. NK cell cytotoxicity was examined using a 51Cr-release assay. The effects of various drugs, including thalidomide, all-trans retinoic acid, dexamethasone, IFN-alpha and incadronate, on the MIC expression and NK cell cytotoxicity were examined. RESULTS: MIC was highly expressed on the human myeloma cell lines U266 and RPMI-8226 and in myeloma cells of one of 10 patients examined. MIC expression on these cells was not changed by various drugs except IFN-alpha, by which MIC expression was down-regulated. Although MIC and HLA class I molecules were similarly expressed at high levels on both cell lines, U266 was sensitive to NK cells whereas RPMI-8226 was not. Furthermore, cytolysis by NK cells was not inhibited by the addition of anti-MIC Ab or decreased expression of MIC caused by IFN-alpha. DISCUSSION: MIC plays a role in the cytolysis by NK cells in multiple myeloma.
