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

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

Author information

1
Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland.
2
Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland. Electronic address: douglas.hanahan@epfl.ch.

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.

PMID:
26412325
DOI:
10.1016/j.ccell.2015.08.012
[Indexed for MEDLINE]
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