title: Irvalec inserts into the plasma membrane causing rapid loss of integrity and necrotic cell death in tumor cells.
abstract: Irvalec is a marine-derived antitumor agent currently undergoing phase II clinical trials. In vitro, Irvalec induces a rapid loss of membrane integrity in tumor cells, accompanied of a significant Ca(2+) influx, perturbations of membrane conductivity, severe swelling and the formation of giant membranous vesicles. All these effects are not observed in Irvalec-resistant cells, or are significantly delayed by pretreating the cells with Zn(2+). Using fluorescent derivatives of Irvalec it was demonstrated that the compound rapidly interacts with the plasma membrane of tumor cells promoting lipid bilayer restructuration. Also, FRET experiments demonstrated that Irvalec molecules localize in the cell membrane close enough to each other as to suggest that the compound could self-organize, forming supramolecular structures that likely trigger cell death by necrosis through the disruption of membrane integrity.
authors.affiliation: Departamento de Biología Celular, PharmaMar S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Molina-Guijarro
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Macías
authors.forename: Carolina
authors.initials: C
authors.lastname: García
authors.forename: Eva
authors.initials: E
authors.lastname: Muñoz
authors.forename: Luis F
authors.initials: LF
authors.lastname: García-Fernández
authors.forename: Miren
authors.initials: M
authors.lastname: David
authors.forename: Lucía
authors.initials: L
authors.lastname: Núñez
authors.forename: Juan F
authors.initials: JF
authors.lastname: Martínez-Leal
authors.forename: Victoria
authors.initials: V
authors.lastname: Moneo
authors.forename: Carmen
authors.initials: C
authors.lastname: Cuevas
authors.forename: M Pilar
authors.initials: MP
authors.lastname: Lillo
authors.forename: Carlos
authors.initials: C
authors.lastname: Villalobos Jorge
authors.forename: Carmen
authors.initials: C
authors.lastname: Valenzuela
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D047630:Depsipeptides / Q000494:pharmacology*; D006801:Humans; D009369:Neoplasms / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C522358:elisidepsin