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Lipid raft-targeted therapy in multiple myeloma

Oncogene volume 29, pages 3748–3757 (2010)Cite this article

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Abstract

Despite recent advances in treatment, multiple myeloma (MM) remains an incurable malignancy. By using in vitro, ex vivo and in vivo approaches, we have identified here that lipid rafts constitute a new target in MM. We have found that the phospholipid ether edelfosine targets and accumulates in MM cell membrane rafts, inducing apoptosis through co-clustering of rafts and death receptors. Raft disruption by cholesterol depletion inhibited drug uptake by tumor cells as well as cell killing. Cholesterol replenishment restored MM cell ability to take up edelfosine and to undergo drug-induced apoptosis. Ceramide addition displaced cholesterol from rafts, and inhibited edelfosine-induced apoptosis. In an MM animal model, edelfosine oral administration showed a potent in vivo antimyeloma activity, and the drug accumulated preferentially and dramatically in the tumor. A decrease in tumor cell cholesterol, a major raft component, inhibited the in vivo antimyeloma action of edelfosine and reduced drug uptake by the tumor. The results reported here provide the proof-of-principle and rationale for further clinical evaluation of edelfosine and for this raft-targeted therapy to improve patient outcome in MM. Our data reveal cholesterol-containing lipid rafts as a novel and efficient therapeutic target in MM, opening a new avenue in cancer treatment.

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Acknowledgements

This work was supported by grants from Ministerio de Ciencia e Innovación (SAF2007-61261, SAF2008-02251, PCT-090100-2007-27, RD06/0020/1037 from Red Temática de Investigación Cooperativa en Cáncer, Instituto de Salud Carlos III), Fondo de Investigación Sanitaria and European Commission (FIS-FEDER 06/0813, PS09/01915), Junta de Castilla y León (GR15-Experimental Therapeutics and Translational Oncology Program, and Biomedicine Project 2009) and Caja Navarra Foundation, Department of Health of the Navarra Government (‘Ortiz de Landázuri, 2009’ project). CG is supported by the Ramón y Cajal Program from the Ministerio de Ciencia e Innovación of Spain. AEHdM is supported by a research grant (BF106.37) from the Department of Education of the Basque Government.

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Authors and Affiliations

  1. Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain

    F Mollinedo, J de la Iglesia-Vicente, C Gajate & J A Villa-Pulgarin

  2. Unidad de Investigación, Hospital Universitario de Salamanca, Campus Miguel de Unamuno, Salamanca, Spain

    C Gajate

  3. Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Navarra, Pamplona, Spain

    A Estella-Hermoso de Mendoza & M J Blanco-Prieto

  4. Servicio de Farmacología Clínica, Clínica Universitaria, Pamplona, Spain

    M A Campanero

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Correspondence to F Mollinedo or C Gajate.

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Mollinedo, F., de la Iglesia-Vicente, J., Gajate, C. et al. Lipid raft-targeted therapy in multiple myeloma. Oncogene 29, 3748–3757 (2010). https://doi.org/10.1038/onc.2010.131

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