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

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-ni...

Full description

Saved in:

Bibliographic Details
Published in:	Toxicology in vitro Vol. 42; pp. 21 - 30
Main Authors:	Marín-Prida, Javier, Pardo Andreu, Gilberto L., Rossignoli, Camila Pederiva, Durruthy, Michael González, Rodríguez, Estael Ochoa, Reyes, Yamila Verdecia, Acosta, Roberto Fernández, Uyemura, Sergio A., Alberici, Luciane C.
Format:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-08-2017 Elsevier Science Ltd
Subjects:	Acetic acid Adenosine triphosphate Adenosine Triphosphate - metabolism Animals Annexin V Antineoplastic Agents - pharmacology Apoptosis ATP Bioenergetics Cancer Cell Survival - drug effects Chemical synthesis Cytotoxicity Dihydropyridine Dihydropyridines - pharmacology Dissipation Electron transport Energy Metabolism - drug effects Fluidity Hep G2 Cells Hepatocellular carcinoma Hepatocytes HepG2 cells Humans Iodides Liver Liver cancer Male Membrane fluidity Membrane potential Membrane Potential, Mitochondrial - drug effects Mitochondria Mitochondria, Liver - drug effects Mitochondria, Liver - metabolism Multidrug resistance Organelles Permeability Potassium Potassium acetate Propidium iodide Rats Rats, Wistar Ruthenium Ruthenium red Toxicity Tumors Uncoupling Uncoupling Agents - pharmacology Valinomycin 1,4-DHP PBS Uncoupling VE-3N Cytotoxicity HepG2 cells CCCP Mitochondria PI MDR Dihydropyridine DPH Cancer
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. •The novel 1,4-dihydropyridine derivative VE-3N induced apoptosis in HepG2 cells.•VE-3N interfered with ATP synthesis by promoting mitochondrial uncoupling.•VE-3N exerted protonophoric action and affected mitochondrial membrane fluidity.•The results help to unravel the cytotoxic mechanisms of 1,4-dihydropyridines towards cancer cells.
ISSN:	0887-2333 1879-3177
DOI:	10.1016/j.tiv.2017.03.011