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Bioorganic & Medicinal Chemistry Letters Jun 2021Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the...
Lactate dehydrogenase (LDH) is a critical enzyme in the glycolytic metabolism pathway that is used by many tumor cells. Inhibitors of LDH may be expected to inhibit the metabolic processes in cancer cells and thus selectively delay or inhibit growth in transformed versus normal cells. We have previously disclosed a pyrazole-based series of potent LDH inhibitors with long residence times on the enzyme. Here, we report the elaboration of a new subseries of LDH inhibitors based on those leads. These new compounds potently inhibit both LDHA and LDHB enzymes, and inhibit lactate production in cancer cell lines.
Topics: Aniline Compounds; Antineoplastic Agents; Cell Line, Tumor; Drug Design; Ethers; Humans; L-Lactate Dehydrogenase
PubMed: 33771585
DOI: 10.1016/j.bmcl.2021.127974 -
International Journal of Biological... Mar 2015The protozoan parasite Cryptosporidium parvum causes waterborne diseases worldwide. There is no effective therapy for C. parvum infection. The parasite depends mainly on...
The protozoan parasite Cryptosporidium parvum causes waterborne diseases worldwide. There is no effective therapy for C. parvum infection. The parasite depends mainly on glycolysis for energy production. Lactate dehydrogenase is a major regulator of glycolysis. This paper describes the biochemical characterization of C. parvum lactate dehydrogenase and high resolution crystal structures of the apo-enzyme and four ternary complexes. The ternary complexes capture the enzyme bound to NAD/NADH or its 3-acetylpyridine analog in the cofactor binding pocket, while the substrate binding site is occupied by one of the following ligands: lactate, pyruvate or oxamate. The results reveal distinctive features of the parasitic enzyme. For example, C. parvum lactate dehydrogenase prefers the acetylpyridine analog of NADH as a cofactor. Moreover, it is slightly less sensitive to gossypol inhibition compared with mammalian lactate dehydrogenases and not inhibited by excess pyruvate. The active site loop and the antigenic loop in C. parvum lactate dehydrogenase are considerably different from those in the human counterpart. Structural features and enzymatic properties of C. parvum lactate dehydrogenase are similar to enzymes from related parasites. Structural comparison with malate dehydrogenase supports a common ancestry for the two genes.
Topics: Amino Acid Sequence; Binding Sites; Cryptosporidium parvum; Enzyme Activation; Kinetics; L-Lactate Dehydrogenase; Models, Molecular; Molecular Sequence Data; NAD; NADP; Protein Binding; Protein Conformation; Sequence Alignment; Substrate Specificity
PubMed: 25542170
DOI: 10.1016/j.ijbiomac.2014.12.019 -
Cancer Control : Journal of the Moffitt... 2021In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted... (Review)
Review
In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling their survival in hypoxic conditions. Altered glucose metabolism of cancer cells includes, inter alia, qualitative and quantitative changes within glucose transporters, enzymes of the glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible factor, monocarboxylate transporters, and lactate dehydrogenase. This review summarizes the current state of knowledge regarding inhibitors of cancer glucose metabolism with a focus on their clinical potential. The altered metabolic phenotype of cancer cells allows for targeting of specific mechanisms, which might improve conventional methods in anti-cancer therapy. However, several problems such as drug bioavailability, specificity, toxicity, the plasticity of cancer cells, and heterogeneity of cells in tumors have to be overcome when designing therapies based on compounds targeted in cancer cell energy metabolism.
Topics: Antineoplastic Agents; Glycolysis; Humans; Hypoxia-Inducible Factor 1; L-Lactate Dehydrogenase; Monocarboxylic Acid Transporters; Neoplasms; Warburg Effect, Oncologic
PubMed: 34554006
DOI: 10.1177/10732748211041243 -
Biomedicine & Pharmacotherapy =... Mar 2022Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain... (Review)
Review
Cancer is one of the main causes of human mortality and brain tumors, including invasive pituitary adenomas, medulloblastomas and glioblastomas are common brain malignancies with poor prognosis. Therefore, the development of innovative management strategies for refractory cancers and brain tumors is important. In states of mitochondrial dysfunction - commonly encountered in malignant cells - cells mostly shift to anaerobic glycolysis by increasing the expression of LDHA (Lactate Dehydrogenase-A) gene. Oxamate, an isosteric form of pyruvate, blocks LDHA activity by competing with pyruvate. By blocking LDHA, it inhibits protumorigenic cascades and also induces ROS (reactive oxygen species)-induced mitochondrial apoptosis of cancer cells. In preclinical studies, oxamate blocked the growth of invasive pituitary adenomas, medulloblastomas and glioblastomas. Oxamate also increases temozolomide and radiotherapy sensitivity of glioblastomas. Oxamate is highly polar, which may preclude its clinical utilization due to low penetrance through cell membranes. However, this obstacle could be overcome with nanoliposomes. Moreover, different oxamate analogs were developed which inhibit LDHC4, an enzyme also involved in cancer progression and germ cell physiology. Lastly, phenformin, an antidiabetic agent, exerts anticancer effects via complex I inhibition in the mitochondria and leading the overproduction of ROS. Oxamate combination with phenformin reduces the lactic acidosis-causing side effect of phenformin while inducing synergistic anticancer efficacy. In sum, oxamate as a single agent and more efficiently with phenformin has high potential to slow the progression of aggressive cancers with special emphasis to brain tumors.
Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Glycolysis; Humans; L-Lactate Dehydrogenase; Mitochondria; Neoplasms; Oxamic Acid; Phenformin; Radiation Tolerance; Reactive Oxygen Species; Temozolomide
PubMed: 35124385
DOI: 10.1016/j.biopha.2022.112686 -
The Journal of Veterinary Medical... Oct 2022Lactate dehydrogenase (LDH) in blood is measured using the Japanese Society of Clinical Chemistry (JSCC) method in Japan and the International Federation of Clinical...
Lactate dehydrogenase (LDH) in blood is measured using the Japanese Society of Clinical Chemistry (JSCC) method in Japan and the International Federation of Clinical Chemistry (IFCC) method in other countries. In human clinical practice, the IFCC method replaced the JSCC method due to international standardization. Moreover, veterinary LDH measurement will also eventually shift to the IFCC method. However, the relationship between the IFCC and JSCC methods for LDH in various animals and whether they can be equated or not have not yet been investigated. This study aimed to present the changes in measurements in canines and felines after switching to the IFCC method. The plasma LDH activity of canines (N=177) and felines (N=115), who visited a secondary care veterinary clinic, was measured using the JSCC and IFCC methods. The IFCC/JSCC ratio was <1.0 in 85% of canines and 88% of felines, indicating that the IFCC method tended to show lower values than the JSCC method, presumably because LDH5 is dominant among the LDH isozymes in canines and felines. The increase in the systematic errors of both assays was in the high value range, with some samples exceeding the error tolerance from near the upper end of the reference range. When switching to the IFCC method for LDH measurement in canines and felines, each institution should consider whether the reference range and clinical diagnostic values established by the JSCC method are appropriate for continued use.
Topics: Animals; Cat Diseases; Cats; Dog Diseases; Dogs; Humans; Isoenzymes; L-Lactate Dehydrogenase; Reference Standards
PubMed: 35934797
DOI: 10.1292/jvms.22-0278 -
d-Lactate Dehydrogenase Links Methylglyoxal Degradation and Electron Transport through Cytochrome c.Plant Physiology Oct 2016Glycolysis generates methylglyoxal (MGO) as an unavoidable, cytotoxic by-product in plant cells. MGO scavenging is performed by the glyoxalase system, which produces...
Glycolysis generates methylglyoxal (MGO) as an unavoidable, cytotoxic by-product in plant cells. MGO scavenging is performed by the glyoxalase system, which produces d-lactate as an end product. d-Lactate dehydrogenase (d-LDH) is encoded by a single gene in Arabidopsis (Arabidopsis thaliana; At5g06580). It catalyzes in vitro the oxidation of d-lactate to pyruvate using flavin adenine dinucleotide as a cofactor; knowledge of its function in the context of the plant cell remains sketchy. Blue native-polyacrylamide gel electrophoresis of mitochondrial extracts combined with in gel activity assays using different substrates and tandem mass spectrometry allowed us to definitely show that d-LDH acts specifically on d-lactate, is active as a dimer, and does not associate with respiratory supercomplexes of the inner mitochondrial membrane. The combined use of cytochrome c (CYTc) loss-of-function mutants and respiratory complex III inhibitors showed that CYTc acts as the in vivo electron acceptor of d-LDH. CYTc loss-of-function mutants, as well as the d-LDH mutants, were more sensitive to d-lactate and MGO, indicating that they function in the same pathway. In addition, overexpression of d-LDH and CYTc increased tolerance to d-lactate and MGO Together with fine-localization of d-LDH, the functional interaction with CYTc in vivo strongly suggests that d-lactate oxidation takes place in the mitochondrial intermembrane space, delivering electrons to the respiratory chain through CYTc These results provide a comprehensive picture of the organization and function of d-LDH in the plant cell and exemplify how the plant mitochondrial respiratory chain can act as a multifunctional electron sink for reductant from cytosolic pathways.
Topics: Arabidopsis; Arabidopsis Proteins; Biocatalysis; Blotting, Western; Cells, Cultured; Cytochromes c; Electron Transport; L-Lactate Dehydrogenase; Lactic Acid; Mass Spectrometry; Microscopy, Confocal; Mitochondrial Membranes; Mutation; Oxidation-Reduction; Oxygen Consumption; Plants, Genetically Modified; Pyruvaldehyde; Pyruvic Acid
PubMed: 27506242
DOI: 10.1104/pp.16.01174 -
BMC Cardiovascular Disorders Sep 2022Lactate dehydrogenase (LDH) has been reported in multiple heart diseases. Herein, we explored the prognostic effects of preoperative LDH on adverse outcomes in cardiac...
BACKGROUND
Lactate dehydrogenase (LDH) has been reported in multiple heart diseases. Herein, we explored the prognostic effects of preoperative LDH on adverse outcomes in cardiac surgery patients.
METHODS
Retrospective data analysis was conducted from two large medical databases: Medical Information Mart for Intensive Care (MIMIC) III and MIMIC IV databases. The primary outcome was in-hospital mortality, whereas the secondary outcomes were 1-year mortality, continuous renal replacement therapy, prolonged ventilation, and prolonged length of intensive care unit and hospital stay.
RESULTS
Patients with a primary endpoint had significantly higher levels of LDH (p < 0.001). Multivariate regression analysis presented that elevated LDH was independently correlated with increased risk of primary and secondary endpoints (all p < 0.001). Subgroup analyses showed that high LDH was consistently associated with primary endpoint. Moreover, LDH exhibited the highest area under the curve (0.768) for the prediction of primary endpoint compared to the other indicators, including neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), lactate, and simplified acute physiology score (SAPS) II. The above results were further confirmed in the MIMIC IV dataset.
CONCLUSIONS
Elevated preoperative LDH may be a robust predictor of poor prognosis in cardiac surgery patients, and its predictive ability is superior to NLR, LMR, PLR, lactate, and SAPS II.
Topics: Cardiac Surgical Procedures; Humans; L-Lactate Dehydrogenase; Lactates; Prognosis; Retrospective Studies
PubMed: 36088306
DOI: 10.1186/s12872-022-02848-7 -
Biomedicine & Pharmacotherapy =... Apr 2023Even though the pathophysiology of colorectal cancer (CRC) is complicated and poorly understood, interactions between risk factors appear to be key in the development... (Review)
Review
Even though the pathophysiology of colorectal cancer (CRC) is complicated and poorly understood, interactions between risk factors appear to be key in the development and progression of the malignancy. The popularity of using lactic acid bacteria (LAB) prebiotics and probiotics to modulate the tumor microenvironment (TME) has grown widely over the past decade. The objective of this study was therefore to determine the detrimental effects of LAB-derived lactic acid in the colonic mucosa in colorectal cancer management. Six library databases and a web search engine were used to execute a structured systematic search of the existing literature, considering all publications published up until August 2022. A total of 7817 papers were screened, all of which were published between 1995 and August 2022. However, only 118 articles met the inclusion criterion. Lactic acid has been directly linked to the massive proliferation of cancerous cells since the glycolytic pathway provides cancerous cells with not only ATP, but also biosynthetic intermediates for rapid growth and proliferation. Our research suggests that targeting LAB metabolic pathways is capable of suppressing tumor growth and that the LDH gene is critical for tumorigenesis. Silencing of Lactate dehydrogenase, A (LDHA), B (LDHB), (LDHL), and hicD genes should be explored to inhibit fermentative glycolysis yielding lactic acid as the by-product. More studies are necessary for a solid understanding of this topic so that LAB and their corresponding lactic acid by-products do not have more adverse effects than their widely touted positive outcomes in CRC management.
Topics: Humans; L-Lactate Dehydrogenase; Glycolysis; Lactic Acid; Colorectal Neoplasms; Probiotics; Tumor Microenvironment
PubMed: 36758316
DOI: 10.1016/j.biopha.2023.114371 -
International Journal of Molecular... Nov 2023Cachexia is a devastating pathology that worsens the quality of life and antineoplastic treatment outcomes of oncologic patients. Herein, we report that the secretome...
Cachexia is a devastating pathology that worsens the quality of life and antineoplastic treatment outcomes of oncologic patients. Herein, we report that the secretome from murine colon carcinoma CT26 induces cachectic features in both murine and human adipocytes that are associated with metabolic alterations such as enhanced lactate production and decreased oxygen consumption. The use of oxamate, which inhibits lactate dehydrogenase activity, hinders the effects induced by CT26 secretome. Interestingly, the CT26 secretome elicits an increased level of lactate dehydrogenase and decreased expression of adiponectin. These modifications are driven by the STAT3 signalling cascade since the inhibition of STAT3 with WP1066 impedes the formation of the cachectic condition and the alteration of lactate dehydrogenase and adiponectin levels. Collectively, these findings show that STAT3 is responsible for the altered lactate dehydrogenase and adiponectin levels that, in turn, could participate in the worsening of this pathology and highlight a step forward in the comprehension of the mechanisms underlying the onset of the cachectic condition in adipocytes.
Topics: Humans; Mice; Animals; Adiponectin; Cachexia; Down-Regulation; Quality of Life; Up-Regulation; Adipocytes; L-Lactate Dehydrogenase; STAT3 Transcription Factor
PubMed: 38003534
DOI: 10.3390/ijms242216343 -
PloS One 2022In recent times, the study of metabolic pathways has become inevitable and predominant for a variety of research fields as cancer biology and immunology. L-lactate as a...
BACKGROUND
In recent times, the study of metabolic pathways has become inevitable and predominant for a variety of research fields as cancer biology and immunology. L-lactate as a product of anaerobic glycolysis has shown to be an important indicator of the cellular metabolic status and can be associated with diverse cellular effects. For this reason, L-lactate assay kits are of high demand when metabolic effects need to be considered. Nevertheless, commercially available kits are not affordable if multiple samples must be evaluated.
PRINCIPAL FINDING
In this work, we develop an easy and cost-effective colorimetric assay for quantification of L-lactate suitable for cells with low or high L-lactate production based on LDH activity and suitable for 96 well-plate format. Using different metabolic regulators, we demonstrate the capacity of the assay to detect and quantify L-lactate from the supernatant of HeLa cancer cell line. Furthermore, we validate the assay against a commercially available kit by demonstrating no significant difference between both assays. Finally, we show that the assay is capable of quantifying L-lactate in primary cells such as hPBMCs that were stimulated with toll-like receptor ligands and treated with different metabolic regulators.
CONCLUSION
We herein present an easy custom assay that is suitable for cells with low and high L-lactate production at very low cost compared to commercially available kits. These advantages of the custom assay can simplify the research in the field of metabolism and related fields.
Topics: Cell Line; Colorimetry; Cost-Benefit Analysis; Glycolysis; L-Lactate Dehydrogenase; Lactic Acid
PubMed: 35867690
DOI: 10.1371/journal.pone.0271818