These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice.
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 Ca uptake, stimulation of Ca 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 Ca 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.
Key indicatorsSingle-crystal X-ray study T = 293 K Mean '(C±C) = 0.004 A Ê R factor = 0.067 wR factor = 0.219 Data-to-parameter ratio = 14.0For details of how these key indicators were automatically derived from the article, see
Key indicatorsSingle-crystal X-ray study T = 293 K Mean '(C±C) = 0.006 A Ê R factor = 0.055 wR factor = 0.167 Data-to-parameter ratio = 12.5For details of how these key indicators were automatically derived from the article, see http://journals.iucr.org/e.
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