The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells

Rosilio, Célia; Lounnas, Nadia; Nebout, Marielle; Imbert, Véronique; Hagenbeek, Thijs J.; Spits, Hergen; Asnafi, Vahid; Pontier-Bres, Rodolphe; Reverso, Julie; Michiels, Jean François; Sahra, Issam Ben; Bost, Fréd́eric; Peyron, Jean François

doi:10.1016/j.canlet.2013.04.015

Cited by 58 publications

(40 citation statements)

References 44 publications

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“…The observation that syrosingopine binds α-enolase could provide a clue to the underlying mechanism. Cancer cells are more vulnerable to mitochondrial inhibition when combined with glucose limitation ( 46 ) or glycolytic inhibition ( 47 , 48 ). Syrosingopine-dependent inhibition of enolase activity, and thus glycolysis, is a plausible mechanism for synthetic lethality with concurrent mitochondrial inhibition.…”

Section: Discussionmentioning

confidence: 99%

Syrosingopine sensitizes cancer cells to killing by metformin

et al. 2016

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Section: Discussionmentioning

confidence: 99%

Syrosingopine sensitizes cancer cells to killing by metformin

et al. 2016

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“…As phenformin appears to be a more potent anticancer drug than metformin in various cell types (11,12,25), we first asked whether the related biguanide phenformin could achieve this same effect with increased potency. Indeed, soft agar assays showed that treatment with metformin or phenformin for 24 h during tamoxifen-induced Src activation reduces the number of colonies to that of cells treated only with vehicle (Fig.…”

Section: Resultsmentioning

confidence: 99%

Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells

Janzer¹,

German

Gonzalez-Herrera

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

238

208

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Metformin, a first-line diabetes drug linked to cancer prevention in retrospective clinical analyses, inhibits cellular transformation and selectively kills breast cancer stem cells (CSCs). Although a few metabolic effects of metformin and the related biguanide phenformin have been investigated in established cancer cell lines, the global metabolic impact of biguanides during the process of neoplastic transformation and in CSCs is unknown. Here, we use LC/MS/MS metabolomics (>200 metabolites) to assess metabolic changes induced by metformin and phenformin in an Src-inducible model of cellular transformation and in mammosphere-derived breast CSCs. Although phenformin is the more potent biguanide in both systems, the metabolic profiles of these drugs are remarkably similar, although not identical. During the process of cellular transformation, biguanide treatment prevents the boost in glycolytic intermediates at a specific stage of the pathway and coordinately decreases tricarboxylic acid (TCA) cycle intermediates. In contrast, in breast CSCs, biguanides have a modest effect on glycolytic and TCA cycle intermediates, but they strongly deplete nucleotide triphosphates and may impede nucleotide synthesis. These metabolic profiles are consistent with the idea that biguanides inhibit mitochondrial complex 1, but they indicate that their metabolic effects differ depending on the stage of cellular transformation.glycolysis | metabolism | cancer metabolism | metabolic profiling A ltered metabolism is a hallmark of malignantly transformed cells. Cancer risk is linked to metabolic syndrome, a disease state that includes obesity, type 2 diabetes, high cholesterol, and atherosclerosis. Retrospective studies of type 2 diabetes patients treated with metformin, the most widely prescribed antidiabetic drug, show a strong correlation between drug intake and reduced tumor incidence or reduced cancer-related deaths (1-4).In the breast lineage, metformin inhibits growth of cancer cell lines (5-7), blocks transformation in a Src-inducible cell system (8, 9), and selectively inhibits the growth of cancer stem cells (CSCs) (8). As a consequence of its selective effects on CSCs, combinatorial therapy of metformin and standard chemotherapeutic drugs (doxorubicin, paclitaxel, and cisplatin) increases tumor regression and prolongs remission in mouse xenografts (8, 10). In addition, metformin can decrease the chemotherapeutic dose for prolonging tumor remission in xenografts involving multiple cancer types (10).Phenformin, a related biguanide and formerly used diabetes drug, acts as an anticancer agent in tumors including lung, lymphoma, and breast cancer with a greater potency than metformin. Phenformin mediates antineoplastic effects at a lower concentration than metformin in cell lines, a PTEN-deficient mouse model, breast cancer xenografts, and drug-induced mitochondrial impairment (11)(12)(13)(14). The chemical similarities of these biguanides, as well as their similar effects in diabetes and cancer, have led to the untested assumption...

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“…Since metformin, a recognized glucose-lowering drug, has been shown to strongly interfere with survival and proliferation on Jurkat cells [25], we wanted to know whether metformin affected the toxicity of ROT in Jurkat cells under G55. As shown in Figure 8(e), metformin increases ~3-fold ROT-induced apoptosis in Jurkat cells in G55, as assessed by AO/EB/Hoechst staining (Figures 8(a)–8(d)), DNA fragmentation (Figure 8(f)), and ΔΨ m depolarization assay (Figure 8(g)).…”

Section: Resultsmentioning

confidence: 99%

Response to Rotenone Is Glucose-Sensitive in a Model of Human Acute Lymphoblastic Leukemia: Involvement of Oxidative Stress Mechanism, DJ-1, Parkin, and PINK-1 Proteins

Mendivil-Perez

Jiménez-Del-Río

Vélez-Pardo

2014

Oxidative Medicine and Cellular Longevity

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To establish the effect of low (11 mM) and high (55 mM) glucose concentrations (G11, G55) on Jurkat cells exposed to rotenone (ROT, a class 5 mitocan). We demonstrated that ROT induces apoptosis in Jurkat cells cultured in G11 by oxidative stress (OS) mechanism involving the generation of anion superoxide radical (O2 ∙−, 68%)/hydrogen peroxide (H2O2, 54%), activation of NF-κB (32%), p53 (25%), c-Jun (17%) transcription factors, and caspase-3 (28%), apoptosis-inducing factor (AIF, 36%) nuclei translocation, c-Jun N-terminal kinase (JNK) activation, and loss of mitochondria transmembrane potential (ΔΨm, 62%) leading to nuclei fragmentation (~10% and ~40% stage I-II fragmented nuclei, resp.). ROT induces massive cytoplasmic aggregates of DJ-1 (93%), and upregulation of Parkin compared to untreated cells, but no effect on PINK-1 protein was observed. Cell death marker detection and DJ-1 and Parkin expression were significantly reduced when cells were cultured in G55 plus ROT. Remarkably, metformin sensitized Jurkat cells against ROT in G55. Our results indicate that a high-glucose milieu promotes resistance against ROT/H2O2-induced apoptosis in Jurkat cells. Our data suggest that combined therapy by using mitochondria-targeted damaging compounds and regulation of glucose (e.g., metformin) can efficiently terminate leukemia cells via apoptosis in hyperglycemic conditions.

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The metabolic perturbators metformin, phenformin and AICAR interfere with the growth and survival of murine PTEN-deficient T cell lymphomas and human T-ALL/T-LL cancer cells

Cited by 58 publications

References 44 publications

Syrosingopine sensitizes cancer cells to killing by metformin

Syrosingopine sensitizes cancer cells to killing by metformin

Metformin and phenformin deplete tricarboxylic acid cycle and glycolytic intermediates during cell transformation and NTPs in cancer stem cells

Response to Rotenone Is Glucose-Sensitive in a Model of Human Acute Lymphoblastic Leukemia: Involvement of Oxidative Stress Mechanism, DJ-1, Parkin, and PINK-1 Proteins

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