Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.
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.
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Silvia
S
Bruno
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Bernardetta
B
Ledda
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Claudya
C
Tenca
Department of Pharmacology, University of Genova, Genova, Italy.
Silvia
S
Ravera
IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Anna Maria
AM
Orengo
Department of Experimental Medicine, University of Genoa, Genoa, Italy.|The Feinstein Institute for Medical Research, North Shore-Long Island, Experimental Immunology, Manhasset, NY, USA.
Andrea Nicola
AN
Mazzarello
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Elisa
E
Pesenti
Department of Internal Medicine and Medical Specialty, University of Genova, Genova, Italy.
Salvatore
S
Casciaro
Hematology-Oncology Unit - Ospedale Villa Scassi, Genova, Italy.
Omar
O
Racchi
Department of Experimental Medicine, University of Genoa, Genoa, Italy.
Fabio
F
Ghiotto
CNR Institute of Bioimages and Molecular Physiology, Milan, Section of Genoa, Genoa, Italy.
Cecilia
C
Marini
IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.|Department of Health Science, University of Genova, Genova, Italy.
Gianmario
G
Sambuceti
Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy.|Division of Medical Oncology, Ospedali Galliera, Genova, Italy.
Andrea
A
DeCensi
Department of Experimental Medicine, University of Genoa, Genoa, Italy.|IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Franco
F
Fais
D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D015398:Signal Transduction
D007004:Hypoglycemic Agents; D008687:Metformin
cancer therapy; cell activation; cell proliferation; chronic lymphocytic leukemia; metformin