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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anticoagulants / administration & dosage
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Anticoagulants / pharmacology
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Antidepressive Agents, Tricyclic / administration & dosage
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Antidepressive Agents, Tricyclic / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Autophagy / drug effects
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Autophagy-Related Protein 7
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / mortality
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Brain Neoplasms / pathology
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Cell Survival / drug effects
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Drug Repositioning
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Drug Synergism
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Gene Knockdown Techniques
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Glioma / drug therapy*
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Glioma / mortality
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Glioma / pathology
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Imipramine / administration & dosage*
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Imipramine / pharmacology
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Mice
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Microtubule-Associated Proteins / genetics
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Survival Analysis
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Ticlopidine / administration & dosage*
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Ticlopidine / pharmacology
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Xenograft Model Antitumor Assays
Substances
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Anticoagulants
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Antidepressive Agents, Tricyclic
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Atg7 protein, mouse
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Microtubule-Associated Proteins
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Autophagy-Related Protein 7
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Imipramine
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Ticlopidine