3‐bromopyruvate inhibits glycolysis, depletes cellular glutathione, and compromises the viability of cultured primary rat astrocytes

Ehrke, Eric; Arend, Christian; Dringen, Ralf

doi:10.1002/jnr.23474

Cited by 40 publications

(19 citation statements)

References 59 publications

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“…These observations are of immediate interest from a clinical point of view. Toxic effects of 2‐DG as well as other glycolytic inhibitors are well known [Dwarakanath et al, ; Ehrke et al, ; Qian et al, ; Raez et al, ]; therefore, introduction of these agents only into specific patients' treatment protocols would allow clinicians to avoid unnecessary side effects and optimize chemotherapeutic regimens.…”

Section: Resultsmentioning

confidence: 99%

Metabolic Suppression of a Drug‐Resistant Subpopulation in Cancer Spheroid Cells

Koshkin

Ailles

Liu³

et al. 2015

J of Cellular Biochemistry

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Inhibition of metabolic features which distinguish cancer cells from their non-malignant counterparts is a promising approach to cancer treatment. Energy support for drug extrusion in multidrug resistance (MDR) is a potential target for metabolic inhibition. Two major sources of ATP-based metabolic energy are partial (glycolysis) and complete (mitochondrial oxidative phosphorylation) oxidation of metabolic fuels. In cancer cells, the balance between them tends to be shifted toward glycolysis; this shift is considered to be characteristic of the cancer metabolic phenotype. Numerous earlier studies, conducted with cells cultured in a monolayer (2-D model), suggested inhibition of glycolytic ATP production as an efficient tool to suppress MDR in cancer cells. Yet, more recent work challenged the appropriateness of the 2-D model for such studies and suggested that a more clinically relevant approach would utilize a more advanced cellular model such as a 3-D model. Here, we show that the transition from the 2-D model (cultured monolayer) to a 3-D model (cultured spheroids) introduces essential changes into the concept of energetic suppression of MDR. The 3-D cell organization leads to the formation of a discrete cell subpopulation (not formed in the 2-D model) with elevated MDR transport capacity. This subpopulation has a specific metabolic phenotype (mixed glycolytic/oxidative MDR support) different from that of cells cultured in the 2-D model. Finally, the shift to the oxidative phenotype becomes greater when the spheroids are grown under conditions of lactic acidosis that are typical for solid tumors. The potential clinical significance of these findings is discussed.

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Section: Resultsmentioning

confidence: 99%

Metabolic Suppression of a Drug‐Resistant Subpopulation in Cancer Spheroid Cells

Koshkin

Ailles

Liu³

et al. 2015

J of Cellular Biochemistry

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“…Rotenone (ROT) decreases mitochondrial electron transfer27, specifically between NADH dehydrogenase and ubiquinone, whereas 2-deoxy-D-glucose (DOG) inhibits glucose uptake through plasma membrane glucose transporters, and iodoacetamide (IODO) reduces the reactivity of glycolysis in sperm242829. 3-Bromopyruvic acid (3BP) inhibits both mitochondrial electron transfer (complex II) and glycolysis including the functions of hexokinase II (HK II) and GAPDH303132333435. The functions of these inhibitors are shown in Table 1.…”

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confidence: 99%

Relationship between Porcine Sperm Motility and Sperm Enzymatic Activity using Paper-based Devices

Matsuura

Huang

Chen

et al. 2017

Sci Rep

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Mammalian sperm motility has traditionally been analyzed to determine fertility using computer-assisted semen analysis (CASA) systems. To develop low-cost and robust male fertility diagnostics, we created a paper-based MTT assay and used it to estimate motile sperm concentration. When porcine sperm motility was inhibited using sperm enzyme inhibitors for sperm enzymes related to mitochondrial activity and glycolysis, we simultaneously recorded sperm motility and enzymatic reactivity using a portable motility analysis system (iSperm) and a paper-based MTT assay, respectively. When using our paper-based MTT-assay, we calculated the area mean value signal intensity (AMV) to evaluate enzymatic reactivity. Both sperm motility and AMV decreased following treatment with iodoacetamide (IODO) and 3-bromopyruvic acid (3BP), both of which are inhibitors of glycolytic enzymes including glyceraldehyde-3-phosphate dehydrogenase (GAPDH). We found a correlation between recorded motility using iSperm and AMV from our paper-based assay (P < 0.05), suggesting that a sperm-related enzymatic reaction is involved in sperm motility. Under this protocol, MTT reduction was coupled with catalysis of GAPDH and was promoted by electron transfer from NADH. Based on this inhibitor study, sperm motility can be estimated using our paper-based MTT-assay.

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“…To further consider the importance of glucose to the parasites, trophozoites were incubated with the glycolytic poison 3-bromopyruvate (3BP) in standard glucosebearing (9 mM glucose) NCM. Inclusion of the compound, which is known to inhibit the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (9), led to reduced cell growth ( Fig. 1B), with only cyst-like structures detectable after 2 days of incubation.…”

Section: Resultsmentioning

confidence: 99%

Enzymatic and Structural Characterization of the Naegleria fowleri Glucokinase

Milanes

Suryadi

Abendroth

et al. 2019

Antimicrob Agents Chemother

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Infection with the free-living amoeba Naegleria fowleri leads to lifethreatening primary amoebic meningoencephalitis. Efficacious treatment options for these infections are limited, and the mortality rate is very high (ϳ98%). Parasite metabolism may provide suitable targets for therapeutic design. Like most other organisms, glucose metabolism is critical for parasite viability, being required for growth in culture. The first enzyme required for glucose metabolism is typically a hexokinase (HK), which transfers a phosphate from ATP to glucose. The products of this enzyme are required for both glycolysis and the pentose phosphate pathway. However, the N. fowleri genome lacks an obvious HK homolog and instead harbors a glucokinase (Glck). The N. fowleri Glck (NfGlck) shares limited (25%) amino acid identity with the mammalian host enzyme (Homo sapiens Glck), suggesting that parasitespecific inhibitors with anti-amoeba activity can be generated. Following heterologous expression, NfGlck was found to have a limited hexose substrate range, with the greatest activity observed with glucose. The enzyme had apparent K m values of 42.5 Ϯ 7.3 M and 141.6 Ϯ 9.9 M for glucose and ATP, respectively. The NfGlck structure was determined and refined to 2.2-Å resolution, revealing that the enzyme shares greatest structural similarity with the Trypanosoma cruzi Glck. These similarities include binding modes and binding environments for substrates. To identify inhibitors of NfGlck, we screened a small collection of inhibitors of glucosephosphorylating enzymes and identified several small molecules with 50% inhibitory concentration values of Ͻ1 M that may prove useful as hit chemotypes for further leads and therapeutic development against N. fowleri.

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3‐bromopyruvate inhibits glycolysis, depletes cellular glutathione, and compromises the viability of cultured primary rat astrocytes

Cited by 40 publications

References 59 publications

Metabolic Suppression of a Drug‐Resistant Subpopulation in Cancer Spheroid Cells

Metabolic Suppression of a Drug‐Resistant Subpopulation in Cancer Spheroid Cells

Relationship between Porcine Sperm Motility and Sperm Enzymatic Activity using Paper-based Devices

Enzymatic and Structural Characterization of the Naegleria fowleri Glucokinase

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