title: Selective inhibition of human TNF-alpha action by flecainide acetate, an antiarrhythmic drug.
abstract: It is now generally accepted that human tumor necrosis factor-alpha (hTNF-alpha) affects not only tumor cells but also normal cells, providing critical tissue damage. hTNF-alpha also enhanced the response of polymorphonuclear neutrophils (PMN) by its priming action and resulted in the increased generation of active oxygen which in turn may be responsible for the tissue injury. Seeking a conventional drug to attenuate the cytolytic activity of tumor necrosis factor (TNF-alpha) and thereby prevent excessive tissue injury, we focused on the cytolytic action of hTNF-alpha against L929 cells, which are sensitive to TNF-alpha, and found that flecainide acetate [N-(2-piperidylmethyl) 1,5-bis-(2,2,2-trifluoroethoxy) benzamide acetate] inhibited specifically the cytolytic action of hTNF-alpha against L929 cells. Flecainide acetate also specifically inhibited the priming action of hTNF-alpha which enhance the formylmethionyl-leucyl-phenylalanine (FMLP)-induced receptor-mediated superoxide (O.2-) generation of human peripheral polymorphonuclear neutrophils (hPMN). The ID50 values for hTNF-alpha induced cytotoxicity in L929 cells and hTNF-alpha primed FMLP-induced O.2- generation of hPMN were 30 and 50-60 microM, respectively. However, the drug does not inhibit the FMLP- or phorbol myristate acetate (PMA)-induced O.2- generation of nonprimed hPMN and has a weak cytotoxic effect on L929 cells. From these results, it is concluded that flecainide acetate suppressed specifically the action of hTNF-alpha.
authors.affiliation: Department of Cell Chemistry, Okayama University Medical School, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Nojima
authors.forename: H
authors.initials: H
authors.lastname: Kobuchi
authors.forename: T
authors.initials: T
authors.lastname: Saibara
authors.forename: T
authors.initials: T
authors.lastname: Yasuda
authors.forename: K
authors.initials: K
authors.lastname: Utsumi
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007739:L Cells; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010750:Phosphoproteins / Q000097:blood / Q000302:isolation & purification; D019000:Phosphotyrosine / Q000032:analysis; D013481:Superoxides / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; D019000:Phosphotyrosine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D005424:Flecainide; D013755:Tetradecanoylphorbol Acetate