The cytotoxic effects of VE-3N, a novel 1,4-dihydropyridine derivative, involve the mitochondrial bioenergetic disruption <i>via</i> uncoupling mechanisms

Marin-Prida, Javier; Pardo Andreu, Gilberto L.; Rossignoli, Camila Pederiva; Gonzalez Durruthy, Michael; Ochoa Rodriguez, Estael; Verdecia Reyes, Yamila; Fernández Acosta, Roberto; Uyemura, Sergio A.; Alberici, Luciane C.

doi:10.1016/J.TIV.2017.03.011

Title

The cytotoxic effects of VE-3N, a novel 1,4-dihydropyridine derivative, involve the mitochondrial bioenergetic disruption via uncoupling mechanisms

Author

Marin-Prida, Javier

Pardo Andreu, Gilberto L.

Rossignoli, Camila Pederiva

Gonzalez Durruthy, Michael

Ochoa Rodriguez, Estael

Verdecia Reyes, Yamila

Fernández Acosta, Roberto

Uyemura, Sergio A.

Alberici, Luciane C.

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-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.

Language

English

Source (journal)

Toxicology in vitro. - Oxford

Publication

Oxford : 2017

ISSN

0887-2333

DOI

10.1016/J.TIV.2017.03.011

Volume/pages

42 (2017) , p. 21-30