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4-Hydroxytamoxifen Inhibits Proliferation of Multiple Myeloma Cells In vitro through Down-Regulation of c-Myc, Up-Regulation of p27^Kip1, and Modulation of Bcl-2 Family Members

¹ UFR de Médecine, Université de Caen-Basse Normandie, Caen, France; ² Institut National de la Santé et de la Recherche Médicale EMI0351, Université Jules Verne, Amiens, France; and ³ Centre National de la Recherche Scientifique, UMR 8612, Université de Paris-Sud, Châtenay-Malabry, France

Requests for reprints: Brigitte Sola, UFR de Médecine, Universté de Caen, CHU Côte de Nacre, 14032 Caen Cedex, France. Phone: 33-2-31068225; Fax: 33-2-31474084; E-mail: sola{at}medecine.unicaen.fr.

Purpose: Multiple myeloma is an incurable B-cell malignancy requiring new therapeutic strategies. Our approach was to analyze the in vitro effects of a selective estrogen receptor modulator, 4-hydroxytamoxifen (4-OHT), on six multiple myeloma cell lines.

Experimental Design: Cultured multiple myeloma cells were treated with various 4-OHT concentrations and the cellular response was studied: cell proliferation, cell viability, induction of apoptosis, caspase activities, and expression of signaling proteins.

Results: We found that pharmacologic concentrations of 4-OHT inhibit cell proliferation (4 of 6 cell lines). This inhibition is achieved by two independent events: a block at the G₁ phase of the cell cycle and the induction of apoptotic death. The cellular response to 4-OHT depends on the presence of functional estrogen receptors. 4-OHT treatment activates an intrinsic mitochondrial caspase-9-dependent pathway but not the Fas/FasL death pathway. Signaling pathways known to be involved in the survival and/or proliferation of multiple myeloma cells are not affected by 4-OHT treatment. 4-OHT-induced G₁ arrest is accompanied by the up-regulation of the cell cycle inhibitor p27^Kip1 and the down-regulation of c-Myc. Among the Bcl-2 family members tested, the proapoptotic BimS protein is induced whereas the antiapoptotic protein Mcl-1 is decreased.

Conclusions: Although the effects of 4-OHT are observed at micromolar concentrations, cellular mechanisms responsible for G₁ arrest, as well as apoptosis induction, are similar to those observed in breast cancer cells. Our data support the concept that 4-OHT may represent an alternative approach to inhibit proliferation and induce apoptosis of multiple myeloma cells.

Key Words: apoptosis • G₁ arrest • estrogen • receptor

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