title: Lidocaine-induced apoptosis and necrosis in U937 cells depending on its dosage.
abstract: Local anesthetics are known to affect a variety of cellular responses other than the action of anesthetics through the Na(+) channel blockade. In this study, we examined the effect of a common local anesthetic lidocaine on the cellular activity and viability of human histiocytic lymphoma U937 cells. The cellular activity and viability were assessed by WST-1 reduction activity and trypan blue exclusion test, respectively. Induction of apoptosis was monitored by DNA ladder formation, reduction of mitochondrial transmembrane potential (DeltaPsim), caspase-3 activity and nuclear morphology. Lidocaine at concentrations below 12 mM induced apoptosis characterized by DNA fragmentation and chromatin condensation dose- and time-dependently. A pan-caspase inhibitor and a caspase-3 inhibitor blocked DNA ladder formation followed by the reduction of cell death. However, the caspase inhibitors did not affect the DeltaPsim, but cyclosporin A inhibited the collapse of DeltaPsim followed by a reduction of cell death. Lidocaine-induced apoptosis was mitochondria- and caspase-dependent, but the collapse of DeltaPsim was independent of caspase activation. At concentrations above 15 mM, lidocaine induced necrosis with early disruption of membrane integrity. These results indicate that lidocaine induced apoptosis and necrosis in U937 cells depending on its dosage.
authors.affiliation: Department of Oral Anesthesiology, Tokyo Dental College, Chiba 261-8502, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Kamiya
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ohta
authors.forename: Yuzuru
authors.initials: Y
authors.lastname: Kaneko
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis / Q000139:chemically induced; D013778:Tetrazolium Salts / Q000494:pharmacology; D020298:U937 Cells
chemical_list: C110656:2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium; D000779:Anesthetics, Local; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D013778:Tetrazolium Salts; D016572:Cyclosporine; D008012:Lidocaine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases