The tricyclic antidepressant imipramine induces autophagic cell death in U-87MG glioma cells

Biochem Biophys Res Commun. 2011 Sep 23;413(2):311-7. doi: 10.1016/j.bbrc.2011.08.093. Epub 2011 Aug 26.

Abstract

In this study, we investigated the antitumor effects of the tricyclic antidepressant 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine (imipramine) on glioma cells. We found that exposure of U-87MG cells to imipramine resulted in the inhibition of PI3K/Akt/mTOR signaling, reduction of clonogenicity, and induction of cell death. Imipramine stimulated the formation of acidic vesicular organelles, the conversion of LC3-I to LC3-II, and the redistribution of LC3 to autophagosomes, suggesting that it stimulates the progression of autophagy. It did not, however, induce apoptosis. We further showed that knockdown of Beclin-1 using siRNA abrogated imipramine-induced cell death. These results suggest that imipramine exerts antitumor effects on PTEN-null U-87MG human glioma cells by inhibiting PI3K/Akt/mTOR signaling and by inducing autophagic cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents, Tricyclic / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis Regulatory Proteins / genetics
  • Autophagy / drug effects*
  • Autophagy / genetics
  • Beclin-1
  • Cell Line, Tumor
  • Gene Knockdown Techniques
  • Glioblastoma / enzymology*
  • Humans
  • Imipramine / pharmacology*
  • Membrane Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • PTEN Phosphohydrolase / genetics
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Rats
  • TOR Serine-Threonine Kinases / antagonists & inhibitors

Substances

  • Antidepressive Agents, Tricyclic
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • light chain 3, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Imipramine