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

A Rodríguez-Lirio,M D Boyano,E Alonso-Tejerina,A Asumendi,G Pérez-Yarza,M R Fernández-Suárez

doi:10.1155/2015/516460

A Rodríguez-Lirio, M D Boyano + Show 4 more

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https://doi.org/10.1155/2015/516460

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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.

Highlights

Acute lymphoblastic leukemia (ALL) types are aggressive hematological cancers, characterized by the uncontrolled clonal proliferation of immature lymphoid cells at different stages of differentiation and their infiltration of the bone marrow [1]
In this study we assessed the antitumor activity of metformin on human ALL cells that are resistant to other antineoplastic drugs, analyzing its capacity to inhibit growth, apoptosis, or autophagy
Our results suggest that the efficacy of metformin against ALL could be related to its ability to disturb the balance between PKCε and PKCδ, two important kinases recently proposed to be crucial for energy homeostasis

Summary

Introduction

Acute lymphoblastic leukemia (ALL) types are aggressive hematological cancers, characterized by the uncontrolled clonal proliferation of immature lymphoid cells at different stages of differentiation and their infiltration of the bone marrow [1]. 15% of pediatric and 25% of adult ALL cases are of T-cell origin (T-ALL) [2], adults diagnosed with T-ALL have a worse prognosis than pediatric patients. This difference has been attributed to the development of higher risk leukemia with greater drug resistance and a worse response to therapy [3, 4]. Resistance to chemotherapy is an important problem in cancer, representing the main reason for therapeutic failure. The resistant phenotype represents an adaptive response of cancer cells and it is characterized by alterations to multiple pathways, among which metabolic alterations might play an important role [6]. In T-ALL, Bcl-2 overexpression or mutations in the PTEN protein are related to resistance [7,8,9,10,11]

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