Title
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The cytotoxic effects of VE-3N, a novel 1,4-dihydropyridine derivative, involve the mitochondrial bioenergetic disruption via uncoupling mechanisms
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Author
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Abstract
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Several 1,4-dihydropyridine derivatives overcome the multidrug resistance in tumors, but their intrinsic cytotoxic mechanisms remain unclear. Here we addressed if mitochondria are involved in the cytotoxicity of the novel 1,4-dihydropyridine derivative VE-3N [ethyl 6-chloro-5-formy1-2-methyl-4-(3-nitropheny1)-1,4-dihydropyridine-3-carboxylate] towards cancer cells by employing hepatic carcinoma (HepG2) cells and isolated rat liver mitochondria. In HepG2 cells, VE-3N induced mitochondrial membrane potential dissipation, ATP depletion, annexin V/propidium iodide double labeling, and Hoechst staining; events indicating apoptosis induction. In isolated rat liver mitochondria, VE-3N promoted mitochondrial uncoupling by exerting protonophoric actions and by increasing membrane fluidity. Mitochondrial uncoupling was evidenced by an increase in resting respiration, dissipation of mitochondrial membrane potential, inhibition of Ca2+ uptake, stimulation of Ca2+ release, decrease in ATP synthesis, and swelling of valinomycin-treated organelles in hyposmotic potassium acetate media. Furthermore, uncoupling concentrations of VE-3N in the presence of Ca2+ plus ruthenium red induced the mitochondrial permeability transition process. These results indicate that mitochondrial uncoupling is potentially involved in the VE-3N cytotoxic actions towards HepG2 cells. Considering that hepatocellular carcinoma is the most common form of liver cancer, our findings may open a new avenue for the development of VE-3N-based cancer therapies, and help to unravel the cytotoxic mechanisms of 1,4-dihydropyridines towards cancer cells. |
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Language
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English
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Source (journal)
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Toxicology in vitro. - Oxford
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Publication
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Oxford
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2017
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ISSN
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0887-2333
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DOI
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10.1016/J.TIV.2017.03.011
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Volume/pages
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42
(2017)
, p. 21-30
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ISI
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000404304900003
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Pubmed ID
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28363597
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Full text (Publisher's DOI)
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Full text (open access)
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