Anti-apoptotic action of (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378) by suppression of the phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and increased phosphorylation of casein kinase2/Akt/ cyclic AMP response element binding protein via maxi-K channel opening in neuronal cells

Eur J Pharmacol. 2004 Aug 30;497(3):267-77. doi: 10.1016/j.ejphar.2004.06.058.

Abstract

This study shows the signaling pathway by which (2S,3S,4R)-N"-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine (KR-31378) prevents tumor necrosis factor (TNF)-alpha-induced neuronal cell death. KR-31378 restored TNF-alpha-induced decreased cell viability of SK-N-SH. U87-MG cells (PTEN-null glioblastoma cell line) transfected with expression vectors for sense PTEN (phosphatase and tensin homolog deleted from chromosome 10) showed significantly decreased cell viability, which was restored by KR-31378. TNF-alpha-induced increased PTEN phosphorylation and decreased phosphorylation of Akt/cyclic AMP response element-binding protein (CREB) in SK-N-SH cells were concentration-dependently reversed by KR-31378, those of which were antagonized by iberiotoxin, a maxi-K channel blocker. TNF-alpha and apigenin, a casein kinase2 (CK2) inhibitor, showed decreased CK2 phosphorylation and increased PTEN phosphorylation, which were reversed by KR-31378. KR-31378 increased K(+) currents by activating the maxi-K channels in SK-N-SH cells, with suppression of TNF-alpha-induced increase in cytosolic Ca(2+) and elevation of suppressed mitochondrial membrane potential, all of which were antagonized by iberiotoxin. It is suggested that increase in cell viability by KR-31378 is ascribed to the maxi-K channel opening-coupled upregulation of CK2/Akt/CREB phosphorylation and downregulation of PTEN phosphorylation in association with increased Bcl-2 and decreased Bax levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Casein Kinase II / metabolism*
  • Cell Survival / drug effects
  • Cyclic AMP / genetics
  • Cyclic AMP / metabolism*
  • Cyclic AMP Response Element-Binding Protein
  • Guanidines / pharmacology*
  • Humans
  • Ion Channel Gating
  • Large-Conductance Calcium-Activated Potassium Channels
  • Membrane Potentials
  • Mitochondria / drug effects
  • Mitochondria / physiology
  • Neurons / cytology
  • Neurons / metabolism*
  • Neurons / physiology
  • PTEN Phosphohydrolase
  • Patch-Clamp Techniques
  • Peptides / pharmacology
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors*
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Potassium Channel Blockers / pharmacology
  • Potassium Channels, Calcium-Activated / metabolism*
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Pyrans / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / antagonists & inhibitors*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism

Substances

  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Guanidines
  • Large-Conductance Calcium-Activated Potassium Channels
  • N''-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N'-benzylguanidine
  • Peptides
  • Potassium Channel Blockers
  • Potassium Channels, Calcium-Activated
  • Proto-Oncogene Proteins
  • Pyrans
  • Transcription Factors
  • Tumor Suppressor Proteins
  • iberiotoxin
  • Cyclic AMP
  • AKT1 protein, human
  • Casein Kinase II
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human