Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit.
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Shchors K
Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland.
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Massaras A
Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland.
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Hanahan D
Swiss Institute for Experimental Cancer Research, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland. Electronic address: douglas.hanahan@epfl.ch.
English
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.
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Language
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Open access status
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bronze
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Persistent URL
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https://sonar.ch/global/documents/69718
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