title: Elisidepsin Interacts Directly with Glycosylceramides in the Plasma Membrane of Tumor Cells to Induce Necrotic Cell Death.
abstract: Plasma membrane integrity is essential for cell life. Any major break on it immediately induces the death of the affected cell. Different molecules were described as disrupting this cell structure and thus showing antitumor activity. We have previously defined that elisidepsin (Irvalec®, PM02734) inserts and self-organizes in the plasma membrane of tumor cells, inducing a rapid loss of membrane integrity, cell permeabilization and necrotic death. Here we show that, in sensitive HCT-116 colorectal cells, all these effects are consequence of the interaction of elisidepsin with glycosylceramides in the cell membrane. Of note, an elisidepsin-resistant subline (HCT-116-Irv) presented reduced levels of glycosylceramides and no accumulation of elisidepsin in the plasma membrane. Consequently, drug treatment did not induce the characteristic necrotic cell death. Furthermore, GM95, a mutant derivative from B16 mouse melanoma cells lacking ceramide glucosyltransferase (UGCG) activity and thus the synthesis of glycosylceramides, was also resistant to elisidepsin. Over-expression of UGCG gene in these deficient cells restored glycosylceramides synthesis, rendering them sensitive to elisidepsin, at a similar level than parental B16 cells. These results indicate that glycosylceramides act as membrane targets of elisidepsin, facilitating its insertion in the plasma membrane and the subsequent membrane permeabilization that leads to drug-induced cell death. They also indicate that cell membrane lipids are a plausible target for antineoplastic therapy.
authors.affiliation: Departamento de Investigación y Desarrollo, PharmaMar S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Molina-Guijarro
authors.affiliation: Departamento de Química Física Biológica, Instituto de Química-Física "Rocasolano" (CSIC), Madrid, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: García
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Macías
authors.affiliation: Departamento de Investigación y Desarrollo, PharmaMar S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Luis Francisco
authors.initials: LF
authors.lastname: García-Fernández
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Moreno
authors.affiliation: Fundación MEDINA, Parque Tecnológico de Ciencias de la Salud, Armilla, Granada, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Reyes
authors.affiliation: Departamento de Investigación y Desarrollo, PharmaMar S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Juan Fernando
authors.initials: JF
authors.lastname: Martínez-Leal
authors.affiliation: Departamento de Investigación y Desarrollo, PharmaMar S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Rogelio
authors.initials: R
authors.lastname: Fernández
authors.affiliation: Departamento de Investigación y Desarrollo, PharmaMar S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Valentín
authors.initials: V
authors.lastname: Martínez
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Valenzuela
authors.affiliation: Departamento de Química Física Biológica, Instituto de Química-Física "Rocasolano" (CSIC), Madrid, Spain.
authors.forename: M Pilar
authors.initials: MP
authors.lastname: Lillo
authors.affiliation: Departamento de Investigación y Desarrollo, PharmaMar S.A., Colmenar Viejo, Madrid, Spain.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Galmarini
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047630:Depsipeptides / Q000494:pharmacology*; D005963:Glucosylceramides / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009336:Necrosis
chemical_list: D047630:Depsipeptides; D005963:Glucosylceramides; C522358:elisidepsin