Desmethylclomipramine induces the accumulation of autophagy markers by blocking autophagic flux

Mario Rossi, Eliana Rosa Munarriz, Stefano Bartesaghi, Marco Milanese, David Dinsdale, Maria Azucena Guerra-Martin, Edward T W Bampton, Paul Glynn, Giambattista Bonanno, Richard A. Knight, Pierluigi Nicotera, Gerry Melino

Research output: Contribution to journalArticle

Abstract

Alterations in the autophagic pathway are associated with the onset and progression of various diseases. However, despite the therapeutic potential for pharmacological modulators of autophagic flux, few such compounds have been characterised. Here we show that clomipramine, an FDA-approved drug long used for the treatment of psychiatric disorders, and its active metabolite desmethylclomipramine (DCMI) interfere with autophagic flux. Treating cells with DCMI caused a significant and specific increase in autophagosomal markers and a concomitant blockage of the degradation of autophagic cargo. This observation might be relevant in therapy in which malignant cells exploit autophagy to survive stress conditions, rendering them more susceptible to the action of cytotoxic agents. In accordance, DCMI-mediated obstruction of autophagic flux increased the cytotoxic effect of chemotherapeutic agents. Collectively, our studies describe a new function of DCMI that can be exploited for the treatment of pathological conditions in which manipulation of autophagic flux is thought to be beneficial.

Original languageEnglish
Pages (from-to)3330-3339
Number of pages10
JournalJournal of Cell Science
Volume122
Issue number18
DOIs
Publication statusPublished - Sep 15 2009

Keywords

  • Anti-depressant
  • Atg5
  • Cell death
  • Chemotherapy
  • Doxorubicin
  • LC3
  • p62 (SQSTM1)

ASJC Scopus subject areas

  • Cell Biology

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