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LDH AND Oxamate

Chrysi Xintaropoulou, Carol Ward, Alan Wise, Suzanna Queckborner, Arran Turnbull, Caroline O Michie, Alistair R W Williams, Tzyvia Rye, Charlie Gourley, Simon P Langdon
BACKGROUND: Novel therapeutic approaches are required to treat ovarian cancer and dependency on glycolysis may provide new targets for treatment. This study sought to investigate the variation of expression of molecular components (GLUT1, HKII, PKM2, LDHA) of the glycolytic pathway in ovarian cancers and the effectiveness of targeting this pathway in ovarian cancer cell lines with inhibitors. METHODS: Expression of GLUT1, HKII, PKM2, LDHA were analysed by quantitative immunofluorescence in a tissue microarray (TMA) analysis of 380 ovarian cancers and associations with clinicopathological features were sought...
June 5, 2018: BMC Cancer
Cara J Valvona, Helen L Fillmore
Medulloblastoma is the most common malignant paediatric brain tumour and current therapies often leave patients with severe neurological disabilities. Four major molecular groups of medulloblastoma have been identified (Wnt, Shh, Group 3 and Group 4), which include additional, recently defined subgroups with different prognosis and genetic characteristics. Lactate dehydrogenase A (LDHA) is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly observed in cancers, associated with tumour progression and metastasis...
March 30, 2018: Brain Sciences
Mona A Abraham, Mozhgan Rasti, Paige V Bauer, Tony K T Lam
The responsiveness of glucose sensing per se to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake in vivo In both rodents and humans, glucose sensing is lost in diabetes and obesity, but the site(s) of impairment remains elusive. Here, we first report that short-term high-fat feeding disrupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat-fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased whole-body glucose tolerance during an intravenous glucose tolerance test...
March 16, 2018: Journal of Biological Chemistry
Yannick Crémillieux, Roberto Salvati, Ursule Dumont, Noël Pinaud, Véronique Bouchaud, Stéphane Sanchez, Stefan Glöggler, Alan Wong
The aims of this study were to implement a magnetic resonance spectroscopy (MRS) protocol for the online profiling of subnanomolar quantities of metabolites sampled from the extracellular fluid using implanted microdialysis and to apply this protocol in glioma-bearing rats for the quantification of lactate concentration and the measurement of time-varying lactate concentration during drug administration. MRS acquisitions on the brain microdialysate were performed using a home-built, proton-tuned, microsolenoid with an active volume of 2 μL...
February 2018: NMR in Biomedicine
Alaa E El-Sisi, Samia S Sokar, Sally E Abu-Risha, Sara R El-Mahrouk
Several human cancers including the breast display elevated expression of Lactate dehydrogenase-A (LDH-A), the enzyme that converts pyruvate to lactate and oxidizes NADH to NAD(+). Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate also plays roles in promoting tumor inflammation and as a signaling molecule that stimulates tumor angiogenesis. Because of its essential role in cancer metabolism, LDH-A has been considered as a potential target for combination cancer therapy...
November 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Gianluca Paventi, Roberto Pizzuto, Salvatore Passarella
Although pig represents a model species in biomedical research including studies dealing with liver patho-physiology, some aspects of liver metabolism need to be addressed. In particular, whether and how pig mitochondria can metabolize l-lactate remains to be established. We show here that pig liver mitochondria (PLM) possess their own l-lactate dehydrogenase (mL-LDH). This was shown both via immunological analysis and by assaying photometrically the L-LDH reaction in solubilised PLM. The mL-LDH reaction shows hyperbolic dependence on the substrate concentration, it is inhibited by oxamate and proves to differ from the cytosolic activity (cL-LDH), as revealed by the difference found in both pH profiles and temperature dependence of m- and cL-LDH...
July 22, 2017: Biochemical and Biophysical Research Communications
Marcella Manerba, Lorenza Di Ianni, Marzia Govoni, Marinella Roberti, Maurizio Recanatini, Giuseppina Di Stefano
In normal cells, heat shock response (HSR) is rapidly induced in response to a variety of harmful conditions and represents one of the most efficient defense mechanism. In cancer tissues, constitutive activation converts HSR into a life-threatening process, which plays a major role in helping cell survival and proliferation. Overexpression of heat shock proteins (HSPs) has been widely reported in human cancers and was found to correlate with tumor progression. Hepatocellular carcinoma is one of the conditions in which HSR activation was shown to have the highest clinical significance...
July 15, 2017: European Journal of Pharmaceutical Sciences
Siavash Mansouri, Ali Shahriari, Hadi Kalantar, Taraneh Moini Zanjani, Mojtaba Haghi Karamallah
High aerobic glycolysis, as one of the hallmarks of cancer cells, requires nicotinamide adenine dinucleotide (NAD(+)) as a vital co-factor, to guarantee the flow of glycolysis. Malate dehydrogenase (MDH), as an important enzyme in cancer metabolism, is a source of NAD(+) additional to lactate dehydrogenase (LDH). The current study aimed to elucidate the kinetic parameters of MDH in human breast cancer and evaluate its supportive role in the glycolysis pathway. The Michaelis-Menten constant (Km) and maximum velocity (Vmax) of MDH were determined in the crude extracts of human breast tumors and healthy tissue samples, which were obtained directly from the operating theatre...
April 2017: Biomedical Reports
Huo-Lei Peng, Robert Callender
Fluorescence of Reduced Nicotinamide Adenine Dinucleotide (NADH) is extensively employed in studies of oxidoreductases. A substantial amount of static and kinetic work has focused on the binding of pyruvate or substrate mimic oxamate to the binary complex of lactate dehydrogenase (LDH)-NADH where substantial fluorescence quenching is typically observed. However, the quenching mechanism is not well understood limiting structural interpretation. Based on time-dependent density functional theory (TDDFT) computations with cam-B3LYP functional in conjunction with the analysis of previous experimental results, we propose that bound oxamate acts as an electron acceptor in the quenching of fluorescence of NADH in the ternary complex, where a charge transfer (CT) state characterized by excitation from the highest occupied molecular orbital (HOMO) of the nicotinamide moiety of NADH to the lowest unoccupied molecular orbital (LUMO) of oxamate exists close to the locally excited (LE) state involving only the nicotinamide moiety...
October 2017: Photochemistry and Photobiology
Verónica García-Castillo, Eduardo López-Urrutia, Octavio Villanueva-Sánchez, Miguel Á Ávila-Rodríguez, Alejandro Zentella-Dehesa, Carlo Cortés-González, César López-Camarillo, Nadia J Jacobo-Herrera, Carlos Pérez-Plasencia
Background: Chemotherapy is the backbone of systemic treatment for triple negative breast cancer (TNBC), which is one of the most relevant breast cancers molecular types due to the ability of tumor cells to develop drug resistance, highlighting the urgent need to design newer and safer drug combinations for treatment. In this context, to overcome tumor cell drug resistance, we employed a novel combinatorial treatment including Doxorubicin, Metformin, and Sodium Oxamate (DoxMetOx). Such pharmacological combination targets indispensable hallmarks of cancer-related to aerobic glycolysis and DNA synthesis...
2017: Journal of Cancer
Álvaro Marín-Hernández, José S Rodríguez-Zavala, Isis Del Mazo-Monsalvo, Sara Rodríguez-Enríquez, Rafael Moreno-Sánchez, Emma Saavedra
Glycolysis provides precursors for the synthesis of macromolecules and may contribute to the ATP supply required for the constant and accelerated cellular duplication in cancer cells. In consequence, inhibition of glycolysis has been reiteratively considered as an anti-cancer therapeutic option. In previous studies, kinetic modeling of glycolysis in cancer cells allowed the identification of the main steps that control the glycolytic flux: glucose transporter, hexokinase (HK), hexose phosphate isomerase (HPI), and glycogen degradation in human cervix HeLa cancer cells and rat AS-30D ascites hepatocarcinoma...
2016: Frontiers in Physiology
Marcella Manerba, Lorenza Di Ianni, Marzia Govoni, Marinella Roberti, Maurizio Recanatini, Giuseppina Di Stefano
The inflammatory microenvironment is an essential component of neoplastic lesions and can significantly impact on tumor progression. Besides facilitating invasive growth, inflammatory cytokines were also found to reprogram cancer cell metabolism and to induce aerobic glycolysis. Previous studies did not consider the possible contribution played in these changes by lactate dehydrogenase (LDH). The A isoform of LDH (LDH-A) is the master regulator of aerobic glycolysis; it actively reduces pyruvate and causes enhanced lactate levels in tumor tissues...
January 1, 2017: European Journal of Pharmaceutical Sciences
Ying-Jr Chen, Nathaniel G Mahieu, Xiaojing Huang, Manmilan Singh, Peter A Crawford, Stephen L Johnson, Richard W Gross, Jacob Schaefer, Gary J Patti
It is well established that lactate secreted by fermenting cells can be oxidized or used as a gluconeogenic substrate by other cells and tissues. It is generally assumed, however, that within the fermenting cell itself, lactate is produced to replenish NAD(+) and then is secreted. Here we explore the possibility that cytosolic lactate is metabolized by the mitochondria of fermenting mammalian cells. We found that fermenting HeLa and H460 cells utilize exogenous lactate carbon to synthesize a large percentage of their lipids...
November 2016: Nature Chemical Biology
Rafael Moreno-Sánchez, Álvaro Marín-Hernández, Isis Del Mazo-Monsalvo, Emma Saavedra, Sara Rodríguez-Enríquez
BACKGROUND: Exceedingly high therapeutic/experimental doses of metabolic drugs such as oxamate, aminooxyacetate (AOA) and dichloroacetate (DCA) are required to diminish growth, glycolysis and oxidative phosphorylation (OxPhos) of different cancer cells. To identify the mechanisms of action of these drugs on cancer energy metabolism, a systematic analysis of their specificities was undertaken. METHODS: Hepatocarcinoma AS-30D cells were treated with the inhibitors and glycolysis and OxPhos enzyme activities, metabolites and fluxes were analyzed...
January 2017: Biochimica et Biophysica Acta
Michael I Koukourakis, Christos Kakouratos, Dimitra Kalamida, Zoi Bampali, Sophia Mavropoulou, Efthimios Sivridis, Alexandra Giatromanolaki
PURPOSE: To assess whether anaerobic metabolism, proliferation activity and stem cell content are linked with radioresistance in bladder cancer. MATERIALS AND METHODS: Tissue sections from 66 patients with invasive transitional cell bladder cancer treated with hypofractionated accelerated radiotherapy, was immunohistochemically analyzed for the Hypoxia-Inducible Factor 1α (HIF1α) and the anaerobic glycolysis enzyme lactate dehydrogenase 5 (LDH5). Proliferation index (Ki-67) and stem-cell marker (cluster of differentiation CD44, aldehyde dehydrogenase ALDH1) expression was also examined...
July 2016: International Journal of Radiation Biology
Qinghua He, Qinglian Zhang, Lin Huang, Jinhu Ma
Lactate dehydrogenase C4 (LDH-C4) is considered to be a target protein for the development of contraceptives. In this work, the characterization of plateau zokor LDH-C4 and the screening of a series of N-substituted oxamic acids as inhibitors against zokor LDH-C4 were reported. The cDNA of zokor LDH-C gene was cloned and expressed in Escherichia coli, from which the protein was purified and further characterized. The protein was a tetramer (LDH-C4) and thermally stable up to 62 °C with a K m of 63.9 μM for pyruvate and with optimal pH values of 7...
July 2016: Applied Biochemistry and Biotechnology
Weiran Ye, Yijia Zheng, Shanshan Zhang, Li Yan, Hua Cheng, Muchao Wu
Oxamate (OXA) is a pyruvate analogue that directly inhibits the lactate dehydrogenase (LDH)-catalyzed conversion process of pyruvate into lactate. Earlier and recent studies have shown elevated blood lactate levels among insulin-resistant and type 2 diabetes subjects and that blood lactate levels independently predicted the development of incident diabetes. To explore the potential of OXA in the treatment of diabetes, db/db mice were treated with OXA in vivo. Treatment of OXA (350-750 mg/kg of body weight) for 12 weeks was shown to decrease body weight gain and blood glucose and HbA1c levels and improve insulin secretion, the morphology of pancreatic islets, and insulin sensitivity in db/db mice...
2016: PloS One
Yang Wang, Lian Wei, Lin-na Wei, Xiao Li, Li-na Xu, Deng-bang Wei
OBJECTIVE: To explore the intergrating of N-isopropyl oxamate and serum protein and establish a high performance liquid chromatography (HPLC) detection method of N-isopropyl oxamate (specific inhibitor of testis-specific lactate dehydrogenase (LDH-C4)) in the blood of plateau pikas. METHODS: Twenty highland pika 150-200 g, were randomly divided into two groups (n = 10): control group and inhibitor group. Different concentrations of N-isopropyl oxamate were added to examine the intergrating of N-isopropyl oxamate and serum protein...
September 2015: Chinese Journal of Applied Physiology
Zhongjian Liu, Yang Sun, Shirui Tan, Liang Liu, Suqiong Hu, Hongyu Huo, Meizhang Li, Qinghua Cui, Min Yu
Although the Warburg effect is a dominant metabolic phenotype observed in cancers, the metabolic changes and adaptation occurring in tumors have been demonstrated to extend beyond the Warburg effect and thus considered a secondary effect to the transformation process of carcinogenesis, including nutritional deficiencies. However, the role of nutritional deficiencies in this metabolic reprogramming (e. g., oxidative phosphorylation (OXPHOS)/glycolysis interconversion) is not completely known yet. Here, we showed that under regular culture condition, the proliferation of U251 cells, but not other tumor cell lines, preferentially performed the Warburg effect and was remarkably inhibited by oxamic acid which can inhibit the activity of lactate dehydrogenase (LDH); whereas under serum starvation, glycolysis was depressed, tricarboxylic acid cycle (TCA) was enhanced, and the activity of OXPHOS was reinforced to maintain cellular ATP content in a high level, but interestingly, we observed a decreased expression of reactive oxygen species (ROS)...
May 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Huo-Lei Peng, Tsuyoshi Egawa, Eric Chang, Hua Deng, Robert Callender
The mechanism of thermal adaptation of enzyme function at the molecular level is poorly understood but is thought to lie within the structure of the protein or its dynamics. Our previous work on pig heart lactate dehydrogenase (phLDH) has determined very high resolution structures of the active site, via isotope edited IR studies, and has characterized its dynamical nature, via laser-induced temperature jump (T-jump) relaxation spectroscopy on the Michaelis complex. These particular probes are quite powerful at getting at the interplay between structure and dynamics in adaptation...
December 10, 2015: Journal of Physical Chemistry. B
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