title: Improved antitumoral properties of pure antiestrogen RU 58668-loaded liposomes in multiple myeloma.
abstract: In most of multiple myeloma (MM) cells, the "pure" antiestrogen (AE) RU 58668 (RU) induced either a G1-arrest (LP-1, OPM-2, NCI-H929, U266 cells) or apoptosis (RPMI 8226 cells). In RPMI 8226 cells, RU activates a caspase-dependent cell death pathway leading to the release of cytochrome c, the decrease of the essential MM survival factor Mcl-1, the cleavage of Bid and the activation of caspases-3 and -8. Incorporation of RU in pegylated cholesterol-containing liposomes allowed a controlled RU release, improving its anti-proliferative and apoptotic effects in cells. In RPMI 8226 xenografts, i.v. injected RU-liposomes but not free RU, exhibited antitumor activity. In vivo, RU-liposomes triggered the mitochondrial death pathway, concomitantly with a down-regulation of Mcl-1 and Bid cleavage. The decrease of CD34 immunoreactivity indicated a reduction of angiogenesis. The decrease of VEGF secretion in vitro supported a direct effect of RU on angiogenesis. These pro-apoptotic and antiangiogenic effects were explained by a prolonged exposure to the drug and to the endocytosis capacity of liposomes which might increase RU uptake and bypass a membrane export of free RU. Thus, these combined enhanced activities of RU-liposomes support that such a delivery of an AE may constitute a strategy of benefit for MM treatment.
authors.affiliation: CNRS UMR 8612, Université de Paris-Sud, Châtenay-Malabry, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Maillard
authors.forename: Juliette
authors.initials: J
authors.lastname: Gauduchon
authors.forename: Véronique
authors.initials: V
authors.lastname: Marsaud
authors.forename: Fabrice
authors.initials: F
authors.lastname: Gouilleux
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Connault
authors.forename: Paule
authors.initials: P
authors.lastname: Opolon
authors.forename: Elias
authors.initials: E
authors.lastname: Fattal
authors.forename: Brigitte
authors.initials: B
authors.lastname: Sola
authors.forename: Jack-Michel
authors.initials: JM
authors.lastname: Renoir
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems / Q000379:methods; D004958:Estradiol / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000302:isolation & purification / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008081:Liposomes; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D014066:Palatine Tonsil / Q000166:cytology; D023041:Xenograft Model Antitumor Assays; D005466:Fluorocarbons
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004958:Estradiol; D004965:Estrogen Antagonists; D020847:Estrogen Receptor Modulators; D008081:Liposomes; C086511:RU 58668; D005466:Fluorocarbons