Oncotarget

Research Papers:

Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells

Silvia Bruno _, Bernardetta Ledda, Claudya Tenca, Silvia Ravera, Anna Maria Orengo, Andrea Nicola Mazzarello, Elisa Pesenti, Salvatore Casciaro, Omar Racchi, Fabio Ghiotto, Cecilia Marini, Gianmario Sambuceti, Andrea DeCensi and Franco Fais

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Oncotarget. 2015; 6:22624-22640. https://doi.org/10.18632/oncotarget.4168

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Abstract

Silvia Bruno1, Bernardetta Ledda1, Claudya Tenca1, Silvia Ravera2, Anna Maria Orengo3, Andrea Nicola Mazzarello1,4, Elisa Pesenti1, Salvatore Casciaro5, Omar Racchi6, Fabio Ghiotto1, Cecilia Marini7, Gianmario Sambuceti3,8, Andrea DeCensi9,10, Franco Fais1,3

1Department of Experimental Medicine, University of Genoa, Genoa, Italy

2Department of Pharmacology, University of Genova, Genova, Italy

3IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy

4The Feinstein Institute for Medical Research, North Shore-Long Island, Experimental Immunology, Manhasset, NY, USA

5Department of Internal Medicine and Medical Specialty, University of Genova, Genova, Italy

6Hematology-Oncology Unit - Ospedale Villa Scassi, Genova, Italy

7CNR Institute of Bioimages and Molecular Physiology, Milan, Section of Genoa, Genoa, Italy

8Department of Health Science, University of Genova, Genova, Italy

9Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy

10Division of Medical Oncology, Ospedali Galliera, Genova, Italy

Correspondence to:

Silvia Bruno, e-mail: silvia.bruno@unige.it

Keywords: metformin, cell proliferation, cell activation, chronic lymphocytic leukemia, cancer therapy

Received: April 02, 2015     Accepted: May 23, 2015     Published: June 05, 2015

ABSTRACT

B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease.

1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients.

Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts.

At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis.

In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules.

Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process.


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