Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Cancer Discovery
Cancer Discovery
  • Home
  • About
    • The Journal
    • AACR Journals
    • Journal Sections
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • Collections
      • COVID-19 & Cancer Resource Center
      • Clinical Trials
      • Immuno-oncology
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
    • Journal Press Releases
  • COVID-19
  • Webinars
  • 10th Anniversary
  • Search More

    Advanced Search

Research Watch

Repurposed Drugs Induce Autophagy-Associated Death in Glioma

DOI: 10.1158/2159-8290.CD-RW2015-188 Published December 2015
  • Article
  • Figures & Data
  • Info & Metrics
Loading
  • 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.

Figure1

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.

Shchors K, Massaras A, Hanahan D. Dual targeting of the autophagic regulatory circuitry in gliomas with repurposed drugs elicits cell-lethal autophagy and therapeutic benefit. Cancer Cell 2015 Sep 24 [Epub ahead of print].

  • ©2015 American Association for Cancer Research.
PreviousNext
Back to top
Cancer Discovery: 5 (12)
December 2015
Volume 5, Issue 12
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover

Sign up for alerts

View this article with LENS

Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Cancer Discovery article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Repurposed Drugs Induce Autophagy-Associated Death in Glioma
(Your Name) has forwarded a page to you from Cancer Discovery
(Your Name) thought you would be interested in this article in Cancer Discovery.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Repurposed Drugs Induce Autophagy-Associated Death in Glioma
Cancer Discov December 1 2015 (5) (12) OF14; DOI: 10.1158/2159-8290.CD-RW2015-188

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Repurposed Drugs Induce Autophagy-Associated Death in Glioma
Cancer Discov December 1 2015 (5) (12) OF14; DOI: 10.1158/2159-8290.CD-RW2015-188
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
  • Figures & Data
  • Info & Metrics
Advertisement

Related Articles

Cited By...

More in this TOC Section

Research Watch

  • In Vivo CRISPR Screen Identifies FLI1 as Regulator of Effector T Cells
  • Trial Supports Combination Treatment and New Target for Multiple Myeloma
  • Mitochondrial DNA Damage Triggers an IFN-Mediated Immune Response
Show more Research Watch

Glioma

  • Distinct Transitional States of Glial Progenitors Drive Gliomagenesis
  • Unique Molecular Landscapes Distinguish Low- and High-Grade NF1 Gliomas
  • (R)-2HG Inhibits the BCAT Transaminase in IDH-Mutant Glioma
Show more Glioma
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook   Twitter   LinkedIn   YouTube   RSS

Articles

  • OnlineFirst
  • Current Issue
  • Past Issues

Info For

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Cancer Discovery

  • About the Journal
  • Editors
  • Journal Sections
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Cancer Discovery
eISSN: 2159-8290
ISSN: 2159-8274

Advertisement