Desmethylclomipramine induces the accumulation of autophagy markers by blocking autophagic flux.
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.
Rossi
Mario
M
Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester LE1 9HN, UK.
Munarriz
Eliana Rosa
ER
Bartesaghi
Stefano
S
Milanese
Marco
M
Dinsdale
David
D
Guerra-Martin
Maria Azucena
MA
Bampton
Edward T W
ET
Glynn
Paul
P
Bonanno
Giambattista
G
Knight
Richard A
RA
Nicotera
Pierluigi
P
Melino
Gerry
G
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
D015415:Biomarkers; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; C012273:desmethylclomipramine; D049452:Green Fluorescent Proteins; D004317:Doxorubicin; D002997:Clomipramine
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