title: Desmethylclomipramine induces the accumulation of autophagy markers by blocking autophagic flux.
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.
authors.affiliation: Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester LE1 9HN, UK.
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.forename: Eliana Rosa
authors.initials: ER
authors.lastname: Munarriz
authors.forename: Stefano
authors.initials: S
authors.lastname: Bartesaghi
authors.forename: Marco
authors.initials: M
authors.lastname: Milanese
authors.forename: David
authors.initials: D
authors.lastname: Dinsdale
authors.forename: Maria Azucena
authors.initials: MA
authors.lastname: Guerra-Martin
authors.forename: Edward T W
authors.initials: ET
authors.lastname: Bampton
authors.forename: Paul
authors.initials: P
authors.lastname: Glynn
authors.forename: Giambattista
authors.initials: G
authors.lastname: Bonanno
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Nicotera
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D002997:Clomipramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D017354:Point Mutation / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013997:Time Factors
chemical_list: D015415:Biomarkers; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; C012273:desmethylclomipramine; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; D002997:Clomipramine
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