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: Sébastien Maillard, Juliette Gauduchon, Véronique Marsaud, Fabrice Gouilleux, Elisabeth Connault, Paule Opolon, Elias Fattal, Brigitte Sola, Jack-Michel Renoir
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 100 Issue 1-3 Pg. 67-78 (Jul 2006) ISSN: 0960-0760 [Print] England
• PMID: 16753295 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Delayed-Action Preparations
• Estrogen Antagonists
• Estrogen Receptor Modulators
• Liposomes
• RU 58668
• Estradiol

Topics

• Animals
• Antineoplastic Agents (isolation & purification, pharmacology)
• Apoptosis (drug effects)
• B-Lymphocytes (cytology, drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cells, Cultured
• Delayed-Action Preparations
• Drug Delivery Systems (methods)
• Estradiol (analogs & derivatives, isolation & purification, pharmacology)
• Estrogen Antagonists (isolation & purification, pharmacology)
• Estrogen Receptor Modulators (administration & dosage, pharmacology)
• Female
• Humans
• Immunohistochemistry
• Liposomes
• Mice
• Mice, Nude
• Models, Biological
• Multiple Myeloma (drug therapy, pathology)
• Palatine Tonsil (cytology)
• Xenograft Model Antitumor Assays