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The Cytotoxic Effects of VE-3N, a Novel 1,4-dihydropyridine Derivative, Involve the Mitochondrial Bioenergetic Disruption via Uncoupling Mechanisms

The Cytotoxic Effects of VE-3N, a Novel 1,4-dihydropyridine Derivative, Involve the Mitochondrial Bioenergetic Disruption via Uncoupling Mechanisms

Javier Marín-Prida, Gilberto L Pardo Andreu, Camila Pederiva Rossignoli, Michael González Durruthy, Estael Ochoa Rodríguez, Yamila Verdecia Reyes, Roberto Fernández Acosta, Sergio A Uyemura, Luciane C Alberici

Toxicol In Vitro. 2017 Aug;42:21-30.

PMID: 28363597

Abstract:

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-formyl-2-methyl-4-(3-nitrophenyl)-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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
LS7931542	Potassium 4-(formyl)benzoyltrifluoroborate			Price

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