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dc.contributor.authorVillanueva Paz, Marina-
dc.contributor.authorCordero, Mario D.-
dc.contributor.authorDelgado Pavón, Ana-
dc.contributor.authorCastejón Vega, Beatriz-
dc.contributor.authorCotán, David-
dc.contributor.authorMata, Mario de la-
dc.contributor.authorOropesa-Ávila, Manuel-
dc.contributor.authorAlcocer-Gómez, Elísabet-
dc.contributor.authorLavera, I. de-
dc.contributor.authorGarrido-Maraver, Juan-
dc.contributor.authorCarrascosa, José-
dc.contributor.authorZaderenko, Paula-
dc.contributor.authorMuntané, Jordi-
dc.contributor.authorMiguel, Manuel de-
dc.contributor.authorSánchez-Alcázar, José Antonio-
dc.date.accessioned2018-04-04T12:02:44Z-
dc.date.available2018-04-04T12:02:44Z-
dc.date.issued2016-
dc.identifierdoi: 10.18632/genesandcancer.114-
dc.identifiere-issn: 1947-6027-
dc.identifierissn: 1947-6019-
dc.identifier.citationGenes and Cancer 7(7-8): 260-277 (2016)-
dc.identifier.urihttp://hdl.handle.net/10261/163149-
dc.description.abstractSystemic treatments for hepatocellular carcinoma (HCC) have been largely unsuccessful. This study investigated the antitumoral activity of Amitriptyline, a tricyclic antidepressant, in hepatoma cells. Amitriptyline-induced toxicity involved early mitophagy activation that subsequently switched to apoptosis. Amitriptyline induced mitochondria dysfunction and oxidative stress in HepG2 cells. Amitriptyline specifically inhibited mitochondrial complex III activity that is associated with decreased mitochondrial membrane potential (ΔΨm) and increased reactive oxygen species (ROS) production. Transmission electron microscopy (TEM) studies revealed structurally abnormal mitochondria that were engulfed by double-membrane structures resembling autophagosomes. Consistent with mitophagy activation, fluorescence microscopy analysis showed mitochondrial Parkin recruitment and colocalization of mitochondria with autophagosome protein markers. Pharmacological or genetic inhibition of autophagy exacerbated the deleterious effects of Amitriptyline on hepatoma cells and led to increased apoptosis. These results suggest that mitophagy acts as an initial adaptive mechanism of cell survival. However persistent mitochondrial damage induced extensive and lethal mitophagy, autophagy stress and autophagolysome permeabilization leading eventually to cell death by apoptosis. Amitriptyline also induced cell death in hepatoma cells lines with mutated p53 and non-sense p53 mutation. Our results support the hypothesis that Amitriptyline-induced mitochondrial dysfunction can be a useful therapeutic strategy for HCC treatment, especially in tumors showing p53 mutations and/or resistant to genotoxic treatments.-
dc.description.sponsorshipThis work was supported by FIS PI13/00129 grant, Ministerio de Sanidad, Spain and Fondo Europeo de Desarrollo Regional (FEDER-Unión Europea), Proyecto de Investigación de Excelencia de la Junta de Andalucía CTS-5725, AEPMI (Asociación de Enfermos de Patología Mitocondrial) and ENACH (Asociación de Enfermedades Neurodegenerativas por Acumulación Cerebral de Hierro).-
dc.publisherImpact Journals-
dc.publisherSage Publications-
dc.relation.isversionofPublisher's version-
dc.rightsopenAccess-
dc.subjectAmitriptyline-
dc.subjectHepG2 cells-
dc.subjectOxidative stress-
dc.subjectApoptosis-
dc.subjectMitophagy-
dc.titleAmitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells-
dc.typeArtículo-
dc.relation.publisherversionhttp://doi.org10.18632/genesandcancer.114-
dc.date.updated2018-04-04T12:02:45Z-
dc.description.versionPeer Reviewed-
dc.language.rfc3066eng-
dc.rights.licensehttp://creativecommons.org/licenses/by/3.0/-
dc.contributor.funderMinisterio de Sanidad, Servicios Sociales e Igualdad (España)-
dc.contributor.funderENACH Asociación-
dc.contributor.funderEuropean Commission-
dc.contributor.funderAsociación de Enfermos de Patologías Mitocondriales (España)-
dc.contributor.funderJunta de Andalucía-
dc.relation.csic-
dc.identifier.funderhttp://dx.doi.org/10.13039/501100000780es_ES
dc.identifier.funderhttp://dx.doi.org/10.13039/501100003751es_ES
dc.identifier.pmid27738496-
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