title: Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells.
abstract: Lung cancer is the most feared of all cancers because of its heterogeneity and resistance to available treatments. Cancer stem cells (CSCs) are the cell population responsible for lung cancer chemoresistance and are a very good model for testing new targeted therapies. Clomipramine is an FDA-approved antidepressant drug, able to inhibit in vitro the E3 ubiquitin ligase Itch and potentiate the pro-apoptotic effects of DNA damaging induced agents in several cancer cell lines. Here, we investigated the potential therapeutic effect of desmethylclomipramine (DCMI), the active metabolite of Clomipramine, on the CSCs homeostasis. We show that DCMI inhibits lung CSCs growth, decreases their stemness potential and increases the cytotoxic effect of conventional chemotherapeutic drugs. Being DCMI an inhibitor of the E3 ubiquitin ligase Itch, we also verified the effect of Itch deregulation on CSCs survival. We found that the siRNA-mediated depletion of Itch induces similar anti-proliferative effects on lung CSCs, suggesting that DCMI might exert its effect, at least in part, by inhibiting Itch. Notably, Itch expression is a negative prognostic factor in two primary lung tumors datasets, supporting the potential clinical relevance of Itch inhibition to circumvent drug resistance in the treatment of lung cancer.
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier, Rome, Italy.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Bongiorno-Borbone
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier, Rome, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Giacobbe
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier, Rome, Italy.
authors.forename: Mirco
authors.initials: M
authors.lastname: Compagnone
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Eramo
authors.affiliation: Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: De Maria
authors.affiliation: Institute of Cell Biology and Neurobiology, CNR, Rome, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Peschiaroli
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Via Montpellier, Rome, Italy.|Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Leicester, United Kingdom.
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002997:Clomipramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D012097:Repressor Proteins; C012273:desmethylclomipramine; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D002997:Clomipramine
keywords: DCMI; Itch inhibitor; chemoresistance; non-small lung cancer stem cells