Priority Research Papers:
Anti-tumoral effect of desmethylclomipramine in lung cancer stem cells
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Lucilla Bongiorno-Borbone1, Arianna Giacobbe1, Mirco Compagnone1, Adriana Eramo2, Ruggero De Maria3, Angelo Peschiaroli4 and Gerry Melino1,5
1 Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Via Montpellier, Rome, Italy
2 Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
3 Regina Elena National Cancer Institute, Rome, Italy
4 Institute of Cell Biology and Neurobiology, CNR, Rome, Italy
5 Medical Research Council, Toxicology Unit, Hodgkin Building, Leicester University, Leicester, United Kingdom
Gerry Melino, email:
Angelo Peschiaroli, email:
Keywords: non-small lung cancer stem cells, Itch inhibitor, DCMI, chemoresistance
Received: June 01, 2015 Accepted: June 21, 2015 Published: July 01, 2015
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.
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