Oncotarget

Research Papers:

Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current

Marta Gritti, Roberto Würth, Marina Angelini, Federica Barbieri, Marta Peretti, Erika Pizzi, Alessandra Pattarozzi, Elisa Carra, Rodolfo Sirito, Antonio Daga, Paul M.G. Curmi, Michele Mazzanti _ and Tullio Florio

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Oncotarget. 2014; 5:11252-11268. https://doi.org/10.18632/oncotarget.2617

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Abstract

Marta Gritti1,*, Roberto Würth2,*, Marina Angelini1,*, Federica Barbieri2, Marta Peretti1, Erika Pizzi1, Alessandra Pattarozzi2, Elisa Carra3, Rodolfo Sirito4, Antonio Daga3, Paul M.G. Curmi5, Michele Mazzanti1 and Tullio Florio2

1 Dipartimento di Bioscienze, University of Milano, Italy

2 Sezione di Farmacologia, Dipartimento di Medicina Interna & Centro di Eccellenza per la Ricerca Biomedica (CEBR), University of Genova, Italy

3 Laboratorio di Trasferimento Genico, IRCCS-AOU San Martino-IST, Genova, Italy

4 Dipartimento di Ostetricia e Ginecologia, Ospedale Evangelico Internazionale, Genova, Italy

5 School of Physics, University of New South Wales, Sydney, Australia

* These authors contributed equally to this work

Correspondence:

Michele Mazzanti, email:

Tullio Florio, email:

Keywords: Metformin, Cancer Stem Cells, Human Glioblastoma, CLIC1, Antitumoral Activity

Received: September 02, 2014 Accepted: October 21, 2014 Published: October 21, 2014

Abstract

Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown.

Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity.

The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin’s antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment.


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