Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells

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

Research output: Contribution to journalArticle

13 Citations (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.

Original languageEnglish
Pages (from-to)16926-16938
Number of pages13
JournalOncotarget
Volume6
Issue number19
Publication statusPublished - 2015

Fingerprint

Neoplastic Stem Cells
Lung Neoplasms
Clomipramine
Ubiquitin-Protein Ligases
Neoplasms
Therapeutic Uses
Drug Resistance
Small Interfering RNA
Antidepressive Agents
Cell Survival
Homeostasis
desmethylclomipramine
Cell Line
Lung
DNA
Growth
Pharmaceutical Preparations
Population

Keywords

  • Chemoresistance
  • DCMI
  • Itch inhibitor
  • Non-small lung cancer stem cells

ASJC Scopus subject areas

  • Oncology

Cite this

Bongiorno-Borbone, L., Giacobbe, A., Compagnone, M., Eramo, A., De Maria, R., Peschiaroli, A., & Melino, G. (2015). Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells. Oncotarget, 6(19), 16926-16938.

Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells. / Bongiorno-Borbone, Lucilla; Giacobbe, Arianna; Compagnone, Mirco; Eramo, Adriana; De Maria, Ruggero; Peschiaroli, Angelo; Melino, Gerry.

In: Oncotarget, Vol. 6, No. 19, 2015, p. 16926-16938.

Research output: Contribution to journalArticle

Bongiorno-Borbone, L, Giacobbe, A, Compagnone, M, Eramo, A, De Maria, R, Peschiaroli, A & Melino, G 2015, 'Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells', Oncotarget, vol. 6, no. 19, pp. 16926-16938.
Bongiorno-Borbone L, Giacobbe A, Compagnone M, Eramo A, De Maria R, Peschiaroli A et al. Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells. Oncotarget. 2015;6(19):16926-16938.
Bongiorno-Borbone, Lucilla ; Giacobbe, Arianna ; Compagnone, Mirco ; Eramo, Adriana ; De Maria, Ruggero ; Peschiaroli, Angelo ; Melino, Gerry. / Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells. In: Oncotarget. 2015 ; Vol. 6, No. 19. pp. 16926-16938.
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