Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas With Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit

Cancer Cell. 2015 Oct 12;28(4):456-471. doi: 10.1016/j.ccell.2015.08.012. Epub 2015 Sep 24.

Abstract

The associations of tricyclic antidepressants (TCAs) with reduced incidence of gliomas and elevated autophagy in glioma cells motivated investigation in mouse models of gliomagenesis. First, we established that imipramine, a TCA, increased autophagy and conveyed modest therapeutic benefit in tumor-bearing animals. Then we screened clinically approved agents suggested to affect autophagy for their ability to enhance imipramine-induced autophagy-associated cell death. The anticoagulant ticlopidine, which inhibits the purinergic receptor P2Y12, potentiated imipramine, elevating cAMP, a modulator of autophagy, reducing cell viability in culture, and increasing survival in glioma-bearing mice. Efficacy of the combination was obviated by knockdown of the autophagic regulatory gene ATG7, implicating cell-lethal autophagy. This seemingly innocuous combination of TCAs and P2Y12 inhibitors may have applicability for treating glioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticoagulants / administration & dosage
  • Anticoagulants / pharmacology
  • Antidepressive Agents, Tricyclic / administration & dosage
  • Antidepressive Agents, Tricyclic / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Autophagy / drug effects
  • Autophagy-Related Protein 7
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Cell Survival / drug effects
  • Drug Repositioning
  • Drug Synergism
  • Gene Knockdown Techniques
  • Glioma / drug therapy*
  • Glioma / mortality
  • Glioma / pathology
  • Imipramine / administration & dosage*
  • Imipramine / pharmacology
  • Mice
  • Microtubule-Associated Proteins / genetics
  • Survival Analysis
  • Ticlopidine / administration & dosage*
  • Ticlopidine / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Anticoagulants
  • Antidepressive Agents, Tricyclic
  • Atg7 protein, mouse
  • Microtubule-Associated Proteins
  • Autophagy-Related Protein 7
  • Imipramine
  • Ticlopidine