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First published online 25 August 2009
doi: 10.1242/jcs.048181

Journal of Cell Science 122, 3330-3339 (2009)
Published by The Company of Biologists 2009
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Research Article

Desmethylclomipramine induces the accumulation of autophagy markers by blocking autophagic flux

Mario Rossi1,*, Eliana Rosa Munarriz1,*, Stefano Bartesaghi1, Marco Milanese2, David Dinsdale1, Maria Azucena Guerra-Martin1, Edward T. W. Bampton1, Paul Glynn1, Giambattista Bonanno2, Richard A. Knight1, Pierluigi Nicotera1 and Gerry Melino1,3,{ddagger}

1 Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester LE1 9HN, UK
2 Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, 16148 Genova, Italy
3 Biochemistry IDI-IRCCS Laboratory, Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy

{ddagger} Author for correspondence (gm89{at}le.ac.uk)

Accepted 30 June 2009

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.

Key words: LC3, Cell death, Anti-depressant, Doxorubicin, Chemotherapy, Atg5, p62 (SQSTM1)


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© The Company of Biologists Ltd 2009