title: Pure antiestrogen-induced G1-arrest in myeloma cells results from the reduced kinase activity of cyclin D3/CDK6 complexes whereas apoptosis is mediated by endoplasmic reticulum-dependent caspases.
abstract: Multiple myeloma (MM) is a malignancy characterized by the accumulation of tumoral plasma cells in bone marrow. This disease remains incurable and the development of new therapeutic strategies is urgently required. We have studied the effects of 2 selective estrogen receptor disrupters (SERDs), RU 58668 (RU) and ICI 182,780 (ICI) or pure antiestrogens (AEs) on MM cell lines. Both compounds have antimyeloma activity through either cell cycle arrest or induction of apoptosis. To analyze the molecular mechanisms of SERD action, we choose 2 differently responding cell lines as models. In LP-1 cells, RU blocked cell cycle at the G1 phase. RU treatment induced a rapid decrease of c-Myc, an upregulation of p27(Kip1), and the subsequent decreased activity of cyclin-dependent kinase, CDK6 and associated cyclin D3, impairing the inactivation of the retinoblastoma protein (pRb). In RPMI 8226 cells, RU induced apoptosis by recruiting endoplasmic reticulum- as well as mitochondria-associated caspases. Moreover, RU interfered with the NF-kappaB survival pathway, often deregulated in MM malignancy. Antimyeloma activities were observed in dexamethasone (Dex)- and RU-resistant cells when RU was combined with bortezomib; Dex and bortezomib being frequently used in MM therapy. RU induced the death of CD138+ cells purified from MM patients but not CD19+ normal cells obtained from tonsils. Therefore, RU mediates the inhibition of survival, the activation of apoptosis and finally potentiates anticancer drug. Those combinatory effects provide a basis for the potential use of pure AEs in MM treatment.
authors.affiliation: Biologie moléculaire et cellulaire de la signalisation, EA 3919, IFR 146, Université de Caen, Caen, Cedex, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Gauduchon
authors.forename: Amélie
authors.initials: A
authors.lastname: Seguin
authors.forename: Véronique
authors.initials: V
authors.lastname: Marsaud
authors.forename: Denis
authors.initials: D
authors.lastname: Clay
authors.forename: Jack-Michel
authors.initials: JM
authors.lastname: Renoir
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sola
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D020169:Caspases / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D003124:Colorimetry; D056743:Cyclin D3; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D008928:Mitochondria / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D005466:Fluorocarbons
chemical_list: D018931:Antineoplastic Agents, Hormonal; D001897:Boronic Acids; D000069286:Bortezomib; D020169:Caspases; D056743:Cyclin D3; D051361:Cyclin-Dependent Kinase 6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D004958:Estradiol; D020847:Estrogen Receptor Modulators; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D020845:Selective Estrogen Receptor Modulators; C534696:CCND3 protein, human; C086511:RU 58668; D005466:Fluorocarbons; C495911:CDK6 protein, human