title: The oncolytic peptide LTX-315 triggers necrotic cell death.
abstract: The oncolytic peptide LTX-315 has been designed for killing human cancer cells and turned out to stimulate anti-cancer immune responses when locally injected into tumors established in immunocompetent mice. Here, we investigated the question whether LTX-315 induces apoptosis or necrosis. Transmission electron microscopy or morphometric analysis of chromatin-stained tumor cells revealed that LTX-315 failed to induce apoptotic nuclear condensation and rather induced a necrotic phenotype. Accordingly, LTX-315 failed to stimulate the activation of caspase-3, and inhibition of caspases by means of Z-VAD-fmk was unable to reduce cell killing by LTX-315. In addition, 2 prominent inhibitors of regulated necrosis (necroptosis), namely, necrostatin-1 and cycosporin A, failed to reduce LTX-315-induced cell death. In conclusion, it appears that LTX-315 triggers unregulated necrosis, which may contribute to its pro-inflammatory and pro-immune effects.
authors.affiliation: a Metabolomics and Cell Biology Platforms; Gustave Roussy Comprehensive Cancer Institute ; Villejuif , France.|b Equipe 11 labellisée Ligue contre le Cancer; Center de Recherche des Cordeliers; INSERM U 1138 ; Paris , France.|c Université Paris Descartes; Sorbonne Paris Cité ; Paris , France.|d Université Pierre et Marie Curie ; Paris , France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Forveille
authors.affiliation: a Metabolomics and Cell Biology Platforms; Gustave Roussy Comprehensive Cancer Institute ; Villejuif , France.|b Equipe 11 labellisée Ligue contre le Cancer; Center de Recherche des Cordeliers; INSERM U 1138 ; Paris , France.|c Université Paris Descartes; Sorbonne Paris Cité ; Paris , France.|d Université Pierre et Marie Curie ; Paris , France.|e University of Paris Sud XI; Kremlin Bicêtre , France.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: a Metabolomics and Cell Biology Platforms; Gustave Roussy Comprehensive Cancer Institute ; Villejuif , France.|b Equipe 11 labellisée Ligue contre le Cancer; Center de Recherche des Cordeliers; INSERM U 1138 ; Paris , France.|c Université Paris Descartes; Sorbonne Paris Cité ; Paris , France.|d Université Pierre et Marie Curie ; Paris , France.
authors.forename: Allan
authors.initials: A
authors.lastname: Sauvat
authors.affiliation: a Metabolomics and Cell Biology Platforms; Gustave Roussy Comprehensive Cancer Institute ; Villejuif , France.|b Equipe 11 labellisée Ligue contre le Cancer; Center de Recherche des Cordeliers; INSERM U 1138 ; Paris , France.|c Université Paris Descartes; Sorbonne Paris Cité ; Paris , France.|d Université Pierre et Marie Curie ; Paris , France.|e University of Paris Sud XI; Kremlin Bicêtre , France.
authors.forename: Lucillia
authors.initials: L
authors.lastname: Bezu
authors.affiliation: a Metabolomics and Cell Biology Platforms; Gustave Roussy Comprehensive Cancer Institute ; Villejuif , France.|b Equipe 11 labellisée Ligue contre le Cancer; Center de Recherche des Cordeliers; INSERM U 1138 ; Paris , France.|c Université Paris Descartes; Sorbonne Paris Cité ; Paris , France.|d Université Pierre et Marie Curie ; Paris , France.|e University of Paris Sud XI; Kremlin Bicêtre , France.
authors.forename: Kevin
authors.initials: K
authors.lastname: Müller
authors.affiliation: a Metabolomics and Cell Biology Platforms; Gustave Roussy Comprehensive Cancer Institute ; Villejuif , France.|b Equipe 11 labellisée Ligue contre le Cancer; Center de Recherche des Cordeliers; INSERM U 1138 ; Paris , France.|c Université Paris Descartes; Sorbonne Paris Cité ; Paris , France.|d Université Pierre et Marie Curie ; Paris , France.|e University of Paris Sud XI; Kremlin Bicêtre , France.
authors.forename: Peng
authors.initials: P
authors.lastname: Liu
authors.affiliation: e University of Paris Sud XI; Kremlin Bicêtre , France.|f Department of Immuno-Oncology ; Institut de Cancérologie Gustave Roussy Cancer Campus ; Villejuif , France.|g Institut National de la Santé et de la Recherche Medicale (INSERM), U1015 ; Villejuif , France.|h Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507 ; Villejuif , France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: i Gustave Roussy Comprehensive Cancer Center; Villejuif; France CNRS; UMR8122 , Villejuif , France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Pierron
authors.affiliation: j University of Tromsø; Institute of Medical Biology ; Tromsø , Norway.|k Lytix Biopharma ; Oslo , Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Rekdal
authors.affiliation: a Metabolomics and Cell Biology Platforms; Gustave Roussy Comprehensive Cancer Institute ; Villejuif , France.|b Equipe 11 labellisée Ligue contre le Cancer; Center de Recherche des Cordeliers; INSERM U 1138 ; Paris , France.|c Université Paris Descartes; Sorbonne Paris Cité ; Paris , France.|d Université Pierre et Marie Curie ; Paris , France.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kepp
authors.affiliation: a Metabolomics and Cell Biology Platforms; Gustave Roussy Comprehensive Cancer Institute ; Villejuif , France.|b Equipe 11 labellisée Ligue contre le Cancer; Center de Recherche des Cordeliers; INSERM U 1138 ; Paris , France.|c Université Paris Descartes; Sorbonne Paris Cité ; Paris , France.|d Université Pierre et Marie Curie ; Paris , France.|l Pôle de Biologie; Hôpital Européen Georges Pompidou; AP-HP ; Paris , France.|m Karolinska Institute ; Department of Women's and Children's Health; Karolinska University Hospital ; Stockholm , Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000648:ultrastructure; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D009336:Necrosis; D009842:Oligopeptides / Q000494:pharmacology*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000648:ultrastructure; D013997:Time Factors
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D007093:Imidazoles; D007211:Indoles; C000609766:LTX-315; D009842:Oligopeptides; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C507699:necrostatin-1; D016572:Cyclosporine
keywords: anticancer immunity, apoptotsis, necrosis, LTX-315