title: Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit.
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.
authors.affiliation: Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland.
authors.forename: Ksenya
authors.initials: K
authors.lastname: Shchors
authors.affiliation: Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland.
authors.forename: Aristea
authors.initials: A
authors.lastname: Massaras
authors.affiliation: Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland. Electronic address: douglas.hanahan@epfl.ch.
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D000071193:Autophagy-Related Protein 7; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D058492:Drug Repositioning; D004357:Drug Synergism; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D007099:Imipramine / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics; D016019:Survival Analysis; D013988:Ticlopidine / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000925:Anticoagulants; D000929:Antidepressive Agents, Tricyclic; C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D000071193:Autophagy-Related Protein 7; D007099:Imipramine; D013988:Ticlopidine