Clozapine, a neuroleptic agent, inhibits Akt by counteracting Ca2+/calmodulin in PTEN-negative U-87MG human glioblastoma cells

Cell Signal. 2006 Nov;18(11):1876-86. doi: 10.1016/j.cellsig.2006.02.004. Epub 2006 Mar 6.


Clozapine (CZP), a dibenzodiazepine derivative with a piperazinyl side chain, is in clinical use as an antipsychotic drug. This study investigated the effect of CZP on the modulation of the PI3K/Akt/GSK-3beta pathway in PTEN-negative U-87MG glioblastoma cells. Treatment with CZP rapidly inhibited the basal and EGF-induced phosphorylation of Akt. The inhibition of Akt resulted in the dephosphorylation of GSK-3beta and increased GSK-3beta kinase activity. A voltage-sensitive Ca(2+) channel blocker and calmodulin (CaM) antagonists inhibited Akt phosphorylation, whereas elevation of the intracellular Ca(2+) concentration prevented CZP-induced dephosphorylation of Akt and GSK-3beta, suggesting that Ca(2+)/CaM participates in the inhibition of Akt by CZP in U-87MG cells. In addition, similar to LY294002, CZP arrested cell cycle progression at G0/G1 phase, which was accompanied by decreased expression of cyclin D1. The reduction in the cyclin D1 level induced by CZP was abrogated by the inhibition of GSK-3beta, the inhibition of proteasome-dependent proteolysis, or an increase in the intracellular Ca(2+) concentration. These results suggest that the antipsychotic drug CZP modulates the PI3K/Akt/GSK-3beta pathway by counteracting Ca(2+)/CaM in PTEN-negative U-87MG glioblastoma cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / pharmacology
  • Calcium / metabolism*
  • Calmodulin / metabolism*
  • Cell Line, Tumor
  • Clozapine / pharmacology*
  • Cytoskeletal Proteins / metabolism
  • Gene Deletion
  • Glioblastoma / drug therapy
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Nuclear Proteins / metabolism
  • PTEN Phosphohydrolase / genetics
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Signal Transduction
  • Tumor Cells, Cultured


  • Antipsychotic Agents
  • Calmodulin
  • Cytoskeletal Proteins
  • NIN protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Clozapine
  • Calcium