title: Nifedipine inhibits activation of transcription factor NF-kappaB.
abstract: This study was performed to examine the effects of the calcium channel blockers, nifedipine, amlodipine, diltiazem, and verapamil on the activation of the transcription factor NF-kappaB. A549 cells, a human epithelium-like lung carcinoma cell line, were transfected with the NF-kappaB reporter plasmid, which contains the luciferase gene driven by promoters containing a TATA element and 5 copies of the kappaB cis-acting element, and co-transfected with 0.2 microg of pSV2neo vector using LipofectAMINE. Nifedipine significantly decreased the expression of luciferase protein stimulated with IL-1beta (1 ng/mL) compared with controls: 80+/-4% at 3 micromol/L, 47+/-2% at 10 micromol/L and 30+/-2% at 30 micromol/L (each, n=3, p<0.0001). The inhibitory effect of nifedipine on promoter activity was concentration-dependent, with a maximal effect obtained at 30 micromol/L. In contrast, high concentrations (30 micromol/L) of amlodipine, diltiazem or verapamil decreased promoter activity to only 89+/-3%, 90+/-3% or 87+/-2% of control, respectively. A comparable inhibitory effect of nifedipine was observed when cells were stimulated with tumor necrosis factor (TNF)-alpha (50 ng/mL), or phorbol 12-myristate 13-acetate (PMA, 100 ng/mL). Electrophoretic mobility shift assay by lipopolysaccharide stimulation, using the RAW 264.7 macrophage cell line, also showed inhibition of NF-kappaB activation by nifedipine in concentrations of 30 and 50 micromol/L. Nifedipine possesses the unique property of inhibiting NF-kappaB, which may be independent of its calcium channel blocking activity, and may, in part, explain its immunosuppressive effect.
authors: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan. amat@kuhp.kyoto-u.ac.jp
authors: A
authors: A
authors: Matsumori
authors: Y
authors: Y
authors: Nunokawa
authors: S
authors: S
authors: Sasayama
mesh_terms: D017311:Amlodipine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002464:Cell Migration Inhibition; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages; D016328:NF-kappa B / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D017311:Amlodipine; D014700:Verapamil; D008156:Luciferases; D004110:Diltiazem; D009543:Nifedipine; D013755:Tetradecanoylphorbol Acetate