Improved antitumoral properties of pure antiestrogen RU 58668-loaded liposomes in multiple myeloma

Sébastien Maillard (1) , Juliette Gauduchon (2) , Véronique Marsaud (1) , Fabrice Gouilleux , Elisabeth Connault (3) , Paule Opolon (3) , Elias Fattal (1) , Brigitte Sola (2) , Jack-Michel Renoir (1)

1 IGPS - Institut Galien Paris-Saclay
2 BMCS - Biologie moléculaire et cellulaire de la signalisation
3 VTG / UMR8121 - Vectorologie et transfert de gènes

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.

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Cancer

Sébastien Maillard, Juliette Gauduchon, Véronique Marsaud, Fabrice Gouilleux, Elisabeth Connault, et al.. Improved antitumoral properties of pure antiestrogen RU 58668-loaded liposomes in multiple myeloma. Journal of Steroid Biochemistry and Molecular Biology, 2006, 100 (1-3), pp.67-78. ⟨10.1016/j.jsbmb.2006.03.008⟩. ⟨hal-02424614⟩