Regulation of Death Induction and Chemosensitizing Action of 3-Bromopyruvate in Myeloid Leukemia Cells: Energy Depletion, Oxidative Stress, and Protein Kinase Activity Modulation

Calviño, Eva; Estañ, María Cristina; Sánchez-Martín, Carlos; Brea, Rocío; Blas, Elena de; Boyano‐Adánez, María del Carmen; Rial, Eduardo; Aller, Patricio

doi:10.1124/jpet.113.206714

Cited by 33 publications

(33 citation statements)

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“…CoA is an important cofactor for intermediary nutrient metabolism and is thought to be involved in up to 4% of all cellular enzymatic reactions (49). Therefore, BrPA has the ability to alter numerous metabolic reactions by pyruvylating thiols, including that of the intracellular reducing agent glutathione (GSH), as proposed earlier (40,50). GSH is important for protecting cells against ROS, and it has been suggested that BrPAmediated cell death is due to oxidative stress (30).…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, a number of studies have reported the anticancer activity of BrPA (26,27,(40)(41)(42)(43)(44)(45)(46), and a modified formula of BrPA was effective at reducing the growth of advanced hepatocellular carcinoma in a human patient (28). However, the metabolic consequences, molecular targets, and mechanism of action for this agent remain unclear.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic Vulnerabilities in Endometrial Cancer

et al. 2014

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Women with metabolic disorders, including obesity and diabetes, have an increased risk of developing endometrial cancer. However, the metabolism of endometrial tumors themselves has been largely understudied. Comparing human endometrial tumors and cells with their nonmalignant counterparts, we found that upregulation of the glucose transporter GLUT6 was more closely associated with the cancer phenotype than other hallmark cancer genes, including hexokinase 2 and pyruvate kinase M2. Importantly, suppression of GLUT6 expression inhibited glycolysis and survival of endometrial cancer cells. Glycolysis and lipogenesis were also highly coupled with the cancer phenotype in patient samples and cells. To test whether targeting endometrial cancer metabolism could be exploited as a therapeutic strategy, we screened a panel of compounds known to target diverse metabolic pathways in endometrial cells. We identified that the glycolytic inhibitor, 3-bromopyruvate, is a powerful antagonist of lipogenesis through pyruvylation of CoA. We also provide evidence that 3-bromopyruvate promotes cell death via a necrotic mechanism that does not involve reactive oxygen species and that 3-bromopyruvate impaired the growth of endometrial cancer xenografts Cancer Res; 74(20); 5832-45. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metabolic Vulnerabilities in Endometrial Cancer

et al. 2014

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“…3-BrP (60 μM) was used as a positive control (see Ref. [44]). The results are expressed in relation to untreated (Cont) cells (approximate GSH content, 8.5 nmol/10 6 cells).…”

Section: Resultsmentioning

confidence: 99%

“…Once we examined protein kinase modulation, the potential importance of these alterations was investigated using appropriate pharmacological inhibitors (the selected concentrations being adopted from our preceding studies with AML cells [44]). The results were as follows: (i) Co-treatment with the PI3K/Akt phosphorylation/activation inhibitors LY294002 (30 μM) or triciribine (10 μM) increased the apoptotic efficacy of 2-DG alone, and also augmented the slight apoptosis obtained with the combination of low concentrations of Quer (10 μM) plus 2-DG (2 mM) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Selected polyphenols potentiate the apoptotic efficacy of glycolytic inhibitors in human acute myeloid leukemia cell lines. Regulation by protein kinase activities

et al. 2016

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BackgroundThe glycolysis inhibitor 2-deoxy-d-glucose (2-DG) is a safe, potentially useful anti-tumour drug, but its efficacy is normally low when used alone. Recent studies indicated that 2-DG stimulates the PI3K/Akt and MEK/ERK defensive pathways, which limits the apoptotic efficacy in tumour cell lines. We hypothesized that co-treatment with selected polyphenols could improve 2-DG-provoked apoptosis by preventing defensive kinase activation.MethodsCell proliferation was measured by cell counting or the MTT assay. Cell cycle, apoptosis and necrosis were determined by propidium iodide staining and/or annexin V labeling followed by flow cytometry. Mitochondria pore transition and depolarization were determined by calcein-ATM or rhodamine 123 labeling followed flow cytometry. Intracellular reactive oxygen species and GSH were determined by dichlorodihydrofluorescein diacetate or monochlorobimane labeling followed by flow cytometry or fluorimetry. Expression and phosphorylation of protein kinases were analyzed by the Western blot.Results(i) 2-DG-provoked apoptosis was greatly potentiated by co-treatment with the sub-lethal concentrations of the flavonoid quercetin in human HL60 acute myeloblastic leukemia cells. Allowing for quantitative differences, apoptosis potentiation was also obtained using NB4 promyelocytic and THP-1 promonocytic cells, using curcumin or genistein instead of quercetin, and using lonidamine instead of 2-DG, but not when 2-DG was substituted by incubation in glucose-free medium. (ii) Quercetin and 2-DG rapidly elicited the opening of mitochondria pore transition, which preceded the trigger of apoptosis. (iii) Treatments did not affect GSH levels, and caused disparate effects on reactive oxygen species generation, which did not match the changes in lethality. (iv) 2-DG and lonidamine stimulated defensive Akt and ERK phosphorylation/activation, while glucose starvation was ineffective. Polyphenols prevented the stimulation of Akt phosphorylation, and in some cases also ERK phosphorylation. In addition, quercetin and 2-DG stimulated GSK-3α,β phosphorylation/inactivation, although with different isoform specificity. The use of pharmacologic inhibitors confirmed the importance of these kinase modifications for apoptosis.ConclusionsThe present in vitro observations suggest that co-treatment with low concentrations of selected polyphenols might represent a manner of improving the poor anti-tumour efficacy of some glycolytic inhibitors, and that apoptosis potentiation may be at least in part explained by the regulation of defensive protein kinase activities.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0345-y) contains supplementary material, which is available to authorized users.

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“…Multiple hematological malignancies, including multiple myeloma [13], acute lymphoblastic leukemia (ALL) [14], chronic lymphatic leukemia (CLL) [15], and AML [16] exhibit increased glucose consumption and upregulated glycolysis. Pharmacological inhibition of glycolysis using 2-deoxyglucose (2-DG) [14, 17] or 3-bromopyruvate [18, 19] can arrest leukemia cell proliferation and synergize with chemotherapeutic agents. Genetic studies in mouse models also support the importance of glycolysis in initiation and maintenance of myeloid malignancies.…”

Section: Increased Glucose Metabolism Supports Anabolism and Redoxmentioning

confidence: 99%

Cell intrinsic and extrinsic regulation of leukemia cell metabolism

Jiang

Nakada

2016

Int J Hematol

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consumption through glycolysis even in the presence of oxygen (aerobic glycolysis) was initially hypothesized to be due to defective mitochondria [2]. However, more recent studies have established that many cancer cells harbor and are dependent upon functional mitochondria [3][4][5][6]. The question why cancer cells preferentially use glycolysis, an uneconomical route to produce ATP compared to mitochondrial oxidative phosphorylation, is beginning to be addressed in cancer cells. Glycolysis is not the dominant mechanism for many cancer cells to produce ATP, and ATP production is not the limiting factor for proliferation [7]. Rather, glycolysis offers cancer cells with metabolites essential for rapid division through metabolic pathways that branch away from glycolysis. For example, glucose-6-phosphate can be diverted to the pentose phosphate pathway (PPP) to produce reducing agents NADPH and ribonucleotides [8]. Additionally, 3-phospho-glycerate can enter the one-carbon cycle to generate amino acids, lipids, and reducing agents [9]. Thus, increased glycolysis meets the demand of proliferative cancer cells for anabolism, producing metabolic intermediates through multiple branching pathways. The decision of how cancer cells divert glycolysis intermediates remains elusive, but it is likely to be affected by cellular metabolic state and the environment in which the cancer cells are exposed.The metabolic milieu of the tumor microenvironment dictates the behavior of tumors. Tumors are exposed to nutrient-and oxygen-poor conditions as they grow exponentially due to insufficient vascularization [10]. Metabolic adaptation to these stress conditions is vital for tumor survival and expansion, and as such multiple metabolic regulators that enable metabolic adaptation are dysregulated in cancer. These include the components of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling that feeds into the mechanistic target of rapamycin (mTOR) pathway, Abstract Metabolic homeostasis is a fundamental property of cells that becomes dysregulated in cancer to meet the altered, often heightened, demand for metabolism for increased growth and proliferation. Oncogenic mutations can directly change cellular metabolism in a cell-intrinsic manner, priming cells for malignancy. Additionally, cellextrinsic cues from the microenvironment, such as hypoxia, nutrient availability, oxidative stress, and crosstalk from surrounding cells can also affect cancer cell metabolism, and produce metabolic heterogeneity within the tumor. Here, we highlight recent findings revealing the complexity and adaptability of leukemia cells to coordinate metabolism.

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Regulation of Death Induction and Chemosensitizing Action of 3-Bromopyruvate in Myeloid Leukemia Cells: Energy Depletion, Oxidative Stress, and Protein Kinase Activity Modulation

Cited by 33 publications

References 53 publications

Metabolic Vulnerabilities in Endometrial Cancer

Metabolic Vulnerabilities in Endometrial Cancer

Selected polyphenols potentiate the apoptotic efficacy of glycolytic inhibitors in human acute myeloid leukemia cell lines. Regulation by protein kinase activities

Cell intrinsic and extrinsic regulation of leukemia cell metabolism

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