Major finding: Induction of autophagy-associated cell death impairs glioma growth and malignant progression.
Mechanism: P2Y12 inhibitors and TCAs cooperate to increase intracellular cAMP, which induces autophagic flux.
Impact: Autophagy enhancers are a potential adjuvant to standard chemotherapy for gliomas.
High-grade gliomas (HGG), which include anaplastic astrocytomas and glioblastomas (GBM), are the most frequent and lethal type of primary brain cancer. However, the current standard-of-care treatment extends patient survival only by months, and thus it is imperative to identify new therapies that confer a more significant survival benefit. To address this clinical need, Shchors and colleagues investigated the mechanism underlying the association of tricyclic antidepressant (TCA) use with decreased incidence of gliomas. Treatment of a p53-deficient genetically engineered mouse model of glioma with the TCA imipramine (IM) resulted in increased overall survival and delayed the progression of low-grade gliomas to HGGs. Histologic examination of IM-treated tumors and glioma cell lines revealed an increase in markers of autophagic flux. To identify agents that enhanced the modest antitumor activity of IM, a drug screen of agents that target distinct nodes of the autophagy pathway was performed. Among the top candidate drugs identified in the screen, only ticlopidine (TIC), an inhibitor of the purinergic receptor P2Y, G-protein coupled 12 (P2Y12), synergized with IM to reduce cell survival in human glioma cell lines and primary mouse GBM cultures. Subsequent characterization of the mechanism of cell death revealed that reduced cell survival was due to enhanced induction of autophagy and not apoptosis or necroptosis. Consistent with these findings, the heightened autophagic flux induced by the combination of IM and TIC reduced the malignant progression of low-grade gliomas to HGGs and increased the survival of late-stage tumor-bearing mice in multiple models of glioma. Dual treatment with IM and TIC cooperatively upregulated cAMP in tumors, which induced autophagy-associated cell death via exchange protein activated by cAMP 1. Together, these results identify coordinated targeting of the autophagic regulatory circuit by FDA-approved TCAs and P2Y12 inhibitors as a potential strategy to treat apoptosis-resistant HGGs.
- ©2015 American Association for Cancer Research.
Volume 5, Issue 12
