RT Journal Article
SR Electronic
T1 Raloxifene-Induced Myeloma Cell Apoptosis: A Study of Nuclear Factor-κB Inhibition and Gene Expression Signature
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1615
OP 1623
DO 10.1124/mol.105.020479
VO 69
IS 5
A1 Sabine Olivier
A1 Pierre Close
A1 Emilie Castermans
A1 Laurence de Leval
A1 Sebastien Tabruyn
A1 Alain Chariot
A1 Michel Malaise
A1 Marie-Paule Merville
A1 Vincent Bours
A1 Nathalie Franchimont
YR 2006
UL http://molpharm.aspetjournals.org/content/69/5/1615.abstract
AB Because multiple myeloma remains associated with a poor prognosis, novel drugs targeting specific signaling pathways are needed. The efficacy of selective estrogen receptor modulators for the treatment of multiple myeloma is not well documented. In the present report, we studied the antitumor activity of raloxifene, a selective estrogen receptor modulator, on multiple myeloma cell lines. Raloxifene effects were assessed by tetrazolium salt reduction assay, cell cycle analysis, and Western blotting. Mobility shift assay, immunoprecipitation, chromatin immunoprecipitation assay, and gene expression profiling were performed to characterize the mechanisms of raloxifene-induced activity. Indeed, raloxifene, as well as tamoxifen, decreased JJN-3 and U266 myeloma cell viability and induced caspase-dependent apoptosis. Raloxifene and tamoxifen also increased the cytotoxic response to vincristine and arsenic trioxide. Moreover, raloxifene inhibited constitutive nuclear factor-κB (NF-κB) activity in myeloma cells by removing p65 from its binding sites through estrogen receptor α interaction with p65. It is noteworthy that microarray analysis showed that raloxifene treatment decreased the expression of known NF-κB-regulated genes involved in myeloma cell survival and myeloma-induced bone lesions (e.g., c-myc, mip-1α, hgf, pac1,...) and induced the expression of a subset of genes regulating cellular cycle (e.g., p21, gadd34, cyclin G2,...). In conclusion, raloxifene induces myeloma cell cycle arrest and apoptosis partly through NF-κB-dependent mechanisms. These findings also provide a transcriptional profile of raloxifene treatment on multiple myeloma cells, offering the framework for future studies of selective estrogen receptor modulators therapy in multiple myeloma.