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Involvement of Mitochondrial Mechanisms in the Cytostatic Effect of Desethylamiodarone in B16F10 Melanoma Cells

Authors
  • Ramadan, Fadi H. J.1
  • Szabo, Aliz1
  • Kovacs, Dominika1
  • Takatsy, Aniko1
  • Bognar, Rita1
  • Gallyas, Ferenc Jr.1, 2, 3
  • Bognar, Zita1
  • 1 (Z.B.)
  • 2 Szentagothai Research Centre, University of Pécs, 7624 Pecs, Hungary
  • 3 HAS-UP Nuclear-Mitochondrial Interactions Research Group, 1245 Budapest, Hungary
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
Oct 05, 2020
Volume
21
Issue
19
Identifiers
DOI: 10.3390/ijms21197346
PMID: 33027919
PMCID: PMC7582344
Source
PubMed Central
Keywords
License
Green

Abstract

Previously, we showed that desethylamiodarone (DEA), a major metabolite of the widely used antiarrhythmic drug amiodarone, has direct mitochondrial effects. We hypothesized that these effects account for its observed cytotoxic properties and ability to limit in vivo metastasis. Accordingly, we examined DEA’s rapid (3–12 h) cytotoxicity and its early (3–6 h) effects on various mitochondrial processes in B16F10 melanoma cells. DEA did not affect cellular oxygen radical formation, as determined using two fluorescent dyes. However, it did decrease the mitochondrial transmembrane potential, as assessed by JC-1 dye and fluorescence microscopy. It also induced mitochondrial fragmentation, as visualized by confocal fluorescence microscopy. DEA decreased maximal respiration, ATP production, coupling efficiency, glycolysis, and non-mitochondrial oxygen consumption measured by a Seahorse cellular energy metabolism analyzer. In addition, it induced a cyclosporine A–independent mitochondrial permeability transition, as determined by Co2+-mediated calcein fluorescence quenching measured using a high-content imaging system. DEA also caused outer mitochondrial membrane permeabilization, as assessed by the immunoblot analysis of cytochrome C, apoptosis inducing factor, Akt, phospho-Akt, Bad, and phospho-Bad. All of these data supported our initial hypothesis.

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