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Title

Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells

AuthorsVillanueva Paz, Marina; Cordero, Mario D. ; Delgado Pavón, Ana; Castejón Vega, Beatriz; Cotán, David ; Mata, Mario de la ; Oropesa-Ávila, Manuel; Alcocer-Gómez, Elísabet; Lavera, I. de; Garrido-Maraver, Juan; Carrascosa, José; Zaderenko, Paula; Muntané, Jordi; Miguel, Manuel de; Sánchez-Alcázar, José Antonio
KeywordsAmitriptyline
HepG2 cells
Oxidative stress
Apoptosis
Mitophagy
Issue Date2016
PublisherImpact Journals
Sage Publications
CitationGenes and Cancer 7(7-8): 260-277 (2016)
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.
Publisher version (URL)http://doi.org10.18632/genesandcancer.114
URIhttp://hdl.handle.net/10261/163149
Identifiersdoi: 10.18632/genesandcancer.114
e-issn: 1947-6027
issn: 1947-6019
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