[en] 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-kappaB (NF-kappaB) activity in myeloma cells by removing p65 from its binding sites through estrogen receptor alpha interaction with p65. It is noteworthy that microarray analysis showed that raloxifene treatment decreased the expression of known NF-kappaB-regulated genes involved in myeloma cell survival and myeloma-induced bone lesions (e.g., c-myc, mip-1alpha, 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-kappaB-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.
Olivier, Sabine ; Université de Liège - ULiège > Département de sciences fonctionnelles > Biochimie et biologie moléculaire
Close, Pierre ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Castermans, Emilie ; Université de Liège - ULiège > Département des sciences cliniques > Département des sciences cliniques
de Leval, Laurence ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Anatomie et cytologie pathologiques - Département des sciences biomédicales et précliniques
Tabruyn, Sébastien ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Chariot, Alain ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Malaise, Michel ; Université de Liège - ULiège > Département des sciences cliniques > Rhumatologie
Merville, Marie-Paule ; Université de Liège - ULiège > Département de pharmacie > Chimie médicale
Bours, Vincent ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique générale et humaine
Franchimont, Nathalie
Language :
English
Title :
Raloxifene-induced myeloma cell apoptosis: a study of nuclear factor-kappaB inhibition and gene expression signature.
Publication date :
May 2006
Journal title :
Molecular Pharmacology
ISSN :
0026-895X
eISSN :
1521-0111
Publisher :
American Society for Pharmacology and Experimental Therapeutics, Bethesda, United States - Maryland
Volume :
69
Issue :
5
Pages :
1615-1623
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Fonds de la Recherche Scientifique (Communauté française de Belgique) - FNRS, TELEVIE, ARC ULG, FBC
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