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.

Metformin Use and Leukemia Risk in Patients With Type 2 Diabetes Mellitus

“…Firstly, in vitro studies usually investigate a specific pathway and ignore the complex actions of and interactions with other biological pathways. Therefore, we cannot readily interpret the findings of metformin benefits on leukemic cells derived from in vitro studies (6,7,11,12). Secondly, an overall neutral effect of metformin on leukemia risk ( Table 2) and the potentially higher risk observed in patients in persistent use (per-protocol analyses, Models VI and VII, Table 3), calls for a cautious attention to the ongoing preclinical trials investigating the use of metformin as a therapeutic agent for leukemia (14).…”

“…Some in vitro studies suggest that metformin may induce cell cycle arrest and apoptosis in leukemic cells (6,7), and leukemic cell growth is activated by the phosphatidylinositol 3-kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) pathway (8,9). Therefore, being recognized for its activating effect on the liver kinase B1/adenosine monophosphate kinase (LKB1/AMPK) resulting in the inhibition of mTOR pathway, metformin theoretically inhibits leukemic cell growth (10,11).…”

HSH2D contributes to methotrexate resistance in�human T‑cell acute lymphoblastic leukaemia

“…At present, the chemotherapy drugs for T-ALL include MTX and etoposide. Although the majority of paediatric patients with T-ALL go into remission after treatment due to the presence of drug-resistant leukaemia cells, 20% of paediatrics do not go into remission, which is a burden on the patients and their families (26,27). Therefore, an in-depth study of the mechanism of T-ALL drug resistance has important social and medical value.…”

Metformin exerts multitarget antileukemia activity in JAK2V617F-positive myeloproliferative neoplasms

“…In addition, preclinical studies already include a range of evidence indicating a potential therapeutic use for metformin in cancer, and clinical trials are currently in progress ( www.clinicaltrials.gov ) 6 . In hematological neoplasms, antineoplastic effects of metformin have been described in chronic myeloid leukemia 17 , 24 , AML 9 , 12 , 25 , 26 , acute lymphoblastic leukemia (ALL) 8 , 16 , 24 , 27 , 28 , chronic lymphocytic leukemia 29 , 30 , lymphoma 15 and multiple myeloma 13 . Importantly, metformin effects appear to act selectively in cancer cells, since cytotoxicity was observed only on leukemia cells and not for colonies from normal hematopoeitic cells 12 , culture of normal peripheral blood mononuclear cells 13 , 14 , normal cord blood CD34 + cells 15 or normal T lymphocytes 16 .…”