title: Metformin Induces Cell Cycle Arrest and Apoptosis in Drug-Resistant Leukemia Cells.
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 Δψ m and it modified the expression of enzymes involved in energy metabolism: PKCε (PKCepsilon) and PKCδ (PKCdelta). In sensitive cells, metformin altered PKCε and PKCδ expression leading to a predominance of PKCε over PKCδ 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.
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Bizkaia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-Lirio
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Bizkaia, Spain.
authors.forename: G
authors.initials: G
authors.lastname: Pérez-Yarza
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Bizkaia, Spain.
authors.forename: M R
authors.initials: MR
authors.lastname: Fernández-Suárez
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Bizkaia, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Alonso-Tejerina
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Bizkaia, Spain.
authors.forename: M D
authors.initials: MD
authors.lastname: Boyano
authors.affiliation: Department of Cell Biology and Histology, School of Medicine and Dentistry, University of the Basque Country, Leioa, 48940 Bizkaia, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Asumendi