Table of Contents
Leukemia Research and Treatment
Volume 2015, Article ID 516460, 12 pages
http://dx.doi.org/10.1155/2015/516460
Research Article

Metformin Induces Cell Cycle Arrest and Apoptosis in Drug-Resistant Leukemia Cells

Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Bizkaia, Spain

Received 17 April 2015; Revised 18 June 2015; Accepted 20 September 2015

Academic Editor: Monique den Boer

Copyright © 2015 A. Rodríguez-Lirio et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Recent epidemiological studies indicate that the antidiabetic drug metformin has chemosensitizing and chemopreventive effects against carcinogenesis. Here, we demonstrate that metformin exerts varying degrees of antitumor activity against human leukemia cells, as reflected by differences in growth inhibition, apoptosis, and alterations to metabolic enzymes. In metformin-sensitive cells, autophagy was not induced but rather it blocked proliferation by means of arresting cells in the S and G2/M phases which was associated with the downregulation of cyclin A, cyclin B1, and cdc2, but not that of cyclin E. In 10E1-CEM cells that overexpress Bcl-2 and are drug-resistant, the effect of metformin on proliferation was more pronounced, also inducing the activation of the caspases 3/7 and hence apoptosis. In all sensitive cells, metformin decreased the and it modified the expression of enzymes involved in energy metabolism: PKC (PKCepsilon) and PKC (PKCdelta). In sensitive cells, metformin altered PKC and PKC expression leading to a predominance of PKC over PKC which implies a more glycolytic state. The opposite occurs in the nonresponsive cells. In conclusion, we provide new insights into the activity of metformin as an antitumoral agent in leukemia cells that could be related to its capability to modulate energy metabolism.