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Villanueva-Paz M, Cordero MD, Pavón AD, et al. Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells. Genes Cancer. 2016;7(7):260-277doi: 10.18632/genesandcancer.114.
Villanueva-Paz, M., Cordero, M. D., Pavón, A. D., Vega, B. C., Cotán, D., De la Mata, M., Oropesa-Ávila, M., Alcocer-Gomez, E., de Lavera, I., Garrido-Maraver, J., Carrascosa, J., Zaderenko, A. P., Muntané, J., de Miguel, M., & Sánchez-Alcázar, J. A. (2016). Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells. Genes & cancer, 7(7), 260-277. https://doi.org/10.18632/genesandcancer.114
Villanueva-Paz, Marina, et al. "Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells." Genes & cancer vol. 7,7 (2016): 260-277. doi: https://doi.org/10.18632/genesandcancer.114
Villanueva-Paz M, Cordero MD, Pavón AD, Vega BC, Cotán D, De la Mata M, Oropesa-Ávila M, Alcocer-Gomez E, de Lavera I, Garrido-Maraver J, Carrascosa J, Zaderenko AP, Muntané J, de Miguel M, Sánchez-Alcázar JA. Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells. Genes Cancer. 2016 Jul;7(7):260-277. doi: 10.18632/genesandcancer.114. PMID: 27738496; PMCID: PMC5059116.
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Genes Cancer. 2016 Jul;7(7):260-277. doi: 10.18632/genesandcancer.114.

Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells.

Genes & cancer

Marina Villanueva-Paz, Mario D Cordero, Ana Delgado Pavón, Beatriz Castejón Vega, David Cotán, Mario De la Mata, Manuel Oropesa-Ávila, Elizabet Alcocer-Gomez, Isabel de Lavera, Juan Garrido-Maraver, José Carrascosa, Ana Paula Zaderenko, Jordi Muntané, Manuel de Miguel, José Antonio Sánchez-Alcázar

Affiliations

  1. Centro Andaluz de Biología de Desarrollo (CABD), Universidad Pablo de Olavide/CSIC/, Sevilla, Spain.
  2. Facultad de Odontología, Universidad de Sevilla, Sevilla, Spain.
  3. Sistemas Físicos, Químicos y Naturales-Universidad Pablo de Olavide, Sevilla, Spain.
  4. Departmento de Cirugía General y Aparato Digestivo, Hospital Universitario Virgen del Rocío/Instituto de Biomedicina de Sevilla (IBiS)/CSIC/Universidad de Sevilla, Sevilla, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
  5. Departamento de Citología e Histología Normal y Patológica, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain.
  6. Centro Andaluz de Biología de Desarrollo (CABD), Universidad Pablo de Olavide/CSIC/, Sevilla, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.

PMID: 27738496 PMCID: PMC5059116 DOI: 10.18632/genesandcancer.114

Abstract

Systemic 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 (∆Ψm) 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.

Keywords: HepG2 cells; amitriptyline; apoptosis; mitophagy; oxidative stress

Conflict of interest statement

The authors declare that they have no conflict of interest.

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