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, Franco Fais

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)22624-22640
Number of pages17
JournalOncotarget
Volume6
Issue number26
Publication statusPublished - 2015

Keywords

  • Cancer therapy
  • Cell activation
  • Cell proliferation
  • Chronic lymphocytic leukemia
  • Metformin

ASJC Scopus subject areas

  • Oncology

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