Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells

Ruggero De Maria Marchiano, Lucilla Bongiorno-Borbone, Arianna Giacobbe, Mirco Compagnone, Adriana Eramo, Angelo Peschiaroli, Gerry Melino

Risultato della ricerca: Contributo in rivistaArticolo in rivista

19 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)16926-16938
Numero di pagine13
RivistaOncotarget
Volume6
DOI
Stato di pubblicazionePubblicato - 2015

Keywords

  • Adenocarcinoma
  • Antineoplastic Agents
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Chemoresistance
  • Clomipramine
  • DCMI
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Humans
  • Itch inhibitor
  • Kaplan-Meier Estimate
  • Lung Neoplasms
  • Neoplastic Stem Cells
  • Non-small lung cancer stem cells
  • Oncology
  • RNA Interference
  • Repressor Proteins
  • Ubiquitin-Protein Ligases

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