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Glycolysis inhibitors

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https://www.readbyqxmd.com/read/27922662/metabolic-reprogramming-and-ampk%C3%AE-1-pathway-activation-by-caulerpin-in-colorectal-cancer-cells
#1
Hua Yu, Huiqin Zhang, Mingjun Dong, Zhou Wu, Zhonglei Shen, Yangyang Xie, Zhenfang Kong, Xiaoyu Dai, Binbin Xu
Caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea is known to induce mitochondrial dysfunctions. In this study, the anticancer property of caulerpin was assessed in a panel of colorectal cancer cell lines. We demonstrated that caulerpin inhibited oxidative phosphorylation (OXPHOS) and facilitated an early intervention of the mitochondrial function, via inhibiting mitochondrial complex I, accompanied by the dissipation of mitochondrial membrane potential and a surge of reactive oxygen species (ROS) generation...
December 6, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27919448/fx11-inhibits-aerobic-glycolysis-and-growth-of-neuroblastoma-cells
#2
Eric J Rellinger, Brian T Craig, Alexandra L Alvarez, Haley L Dusek, Kwang W Kim, Jingbo Qiao, Dai H Chung
BACKGROUND: The MYC family of proteins promotes neuroblastoma tumorigenesis at least in part through the induction of aerobic glycolysis by promoting the transcription of key glycolytic enzymes, such as LDHA. FX11 is a selective inhibitor of LDHA that has demonstrated preclinical efficacy in adult cancers. Herein, we hypothesized that FX11 would inhibit aerobic glycolysis and block growth of neuroblastoma cells. METHODS: We surveyed 3 MYCN-single copy and 5 MYCN-amplified neuroblastoma cell lines to correlate C-MYC/N-MYC protein levels with LDHA expression...
December 2, 2016: Surgery
https://www.readbyqxmd.com/read/27912096/drugging-acat1-for-cancer-therapy
#3
Javier Garcia-Bermudez, Kivanç Birsoy
In this issue, Fan et al. (2016) show that oncogenic tyrosine kinases can promote glycolysis by phosphorylating and stabilizing the tetrameric form of mitochondrial acetyl-coA acetyltransferase 1 (ACAT1). The authors further identify a small molecule ACAT1 inhibitor that displays anti-cancer effects.
December 1, 2016: Molecular Cell
https://www.readbyqxmd.com/read/27906635/a-specific-inhibitor-of-lactate-dehydrogenase-overcame-the-resistance-toward-gemcitabine-in-hypoxic-mesothelioma-cells-and-modulated-the-expression-of-the-human-equilibrative-transporter-1
#4
Elisa Giovannetti, Leticia G Leon, Valentina E Gómez, Paolo A Zucali, Filippo Minutolo, Godefridus J Peters
Malignant pleural mesothelioma (MPM) is a very hypoxic malignancy, and hypoxia has been associated with resistance towards gemcitabine. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis. Therefore we investigated the combination of a new LDH-A inhibitor (NHI-1) with gemcitabine in MPM cell lines. Under hypoxia (O2 tension of 1%) the cell growth inhibitory effects of gemcitabine, were reduced, as demonstrated by a 5- to 10-fold increase in IC50s...
December 2016: Nucleosides, Nucleotides & Nucleic Acids
https://www.readbyqxmd.com/read/27904682/targeting-cancer-cell-metabolism-the-combination-of-metformin-and-2-deoxyglucose-regulates-apoptosis-in-ovarian-cancer-cells-via-p38-mapk-jnk-signaling-pathway
#5
Jie Zhu, Ya Zheng, Haiyan Zhang, Hong Sun
Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a first-line treatment for type 2 diabetes mellitus, exerts anti-cancer and anti-proliferative action. 2-deoxyglucose (2-DG), a glucose analog, works as a competitive inhibitor of glycolysis. In this study, we show for the first time that metformin in combination with 2-DG inhibited growth, migration, invasion and induced cell cycle arrest of ovarian cancer cells in vitro. Moreover, metformin and 2-DG could efficiently induce apoptosis in ovarian cancer cells, which was achieved by activating p38 MAPK and JNK pathways...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27903739/homocysteine-activates-b-cells-via-regulating-pkm2-dependent-metabolic-reprogramming
#6
Jiacheng Deng, Silin Lü, Huiying Liu, Bo Liu, Changtao Jiang, Qingbo Xu, Juan Feng, Xian Wang
The overactivation of immune cells plays an important role in the pathogenesis of hyperhomocysteinemia (HHcy)-accelerated atherosclerosis. Homocysteine (Hcy) activates B cell proliferation and Ab secretion; however, the underlying mechanisms for these effects remain largely unknown. Metabolic reprogramming is critical for lymphocyte activation and effector function. In this study, we showed that Hcy-activated B cells displayed an increase in both oxidative phosphorylation and glycolysis, with a tendency to shift toward the latter, as well as an accumulation of intermediates in the pentose phosphate pathway, to provide energy and biosynthetic substrates for cell growth and function...
November 30, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27894844/the-tricarboxylic-acid-cycle-activity-in-cultured-primary-astrocytes-is-strongly-accelerated-by-the-protein-tyrosine-kinase-inhibitor-tyrphostin-23
#7
Michaela C Hohnholt, Eva-Maria Blumrich, Helle S Waagepetersen, Ralf Dringen
Tyrphostin 23 (T23) is a well-known inhibitor of protein tyrosine kinases and has been considered as potential anti-cancer drug. T23 was recently reported to acutely stimulate the glycolytic flux in primary cultured astrocytes. To investigate whether T23 also affects the tricarboxylic acid (TCA) cycle, we incubated primary rat astrocyte cultures with [U-(13)C]glucose in the absence or the presence of 100 μM T23 for 2 h and analyzed the (13)C metabolite pattern. These incubation conditions did not compromise cell viability and confirmed that the presence of T23 doubled glycolytic lactate production...
November 25, 2016: Neurochemistry International
https://www.readbyqxmd.com/read/27894252/transcriptome-analysis-reveals-the-genetic-basis-underlying-the-seasonal-development-of-keratinized-nuptial-spines-in-leptobrachium-boringii
#8
Wei Zhang, Yue Guo, Jun Li, Li Huang, Eric Gilbert Kazitsa, Hua Wu
BACKGROUND: The expression of sexually selected traits often varies with populations' breeding cycles in many animals. The elucidation of mechanisms underlying the expression of such traits is a research topic in evolutionary biology; however, the genetic basis of the seasonal development of their expression remains unknown. Male Leptobrachium boringii develop keratinized nuptial spines on their upper jaw during the breeding season that fall off when the breeding season ends. To illuminate the genetic basis for the expression of this trait and its seasonal development, we assessed the de novo transcriptome for L...
November 28, 2016: BMC Genomics
https://www.readbyqxmd.com/read/27884166/tigar-cooperated-with-glycolysis-to-inhibit-the-apoptosis-of-leukemia-cells-and-associated-with-poor-prognosis-in-patients-with-cytogenetically-normal-acute-myeloid-leukemia
#9
Sixuan Qian, Jianyong Li, Ming Hong, Yu Zhu, Huihui Zhao, Yue Xie, Jiayu Huang, Yun Lian, Yanru Li, Shuai Wang, Jianping Mao, Yaoyu Chen
BACKGROUND: Cancer cells show increased glycolysis and take advantage of this metabolic pathway to generate ATP. The TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits aerobic glycolysis and protects tumor cells from intracellular reactive oxygen species (ROS)-associated apoptosis. However, the function of TIGAR in glycolysis and survival of acute myeloid leukemia cells remains unclear. METHODS: We analyzed TIGAR expression in cytogenetically normal (CN-) AML patients and the correlations with clinical and biological parameters...
November 25, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27864140/the-role-of-mir-190a-in-methylglyoxal-induced-insulin-resistance-in-endothelial-cells
#10
Paola Mirra, Cecilia Nigro, Immacolata Prevenzano, Teresa Procopio, Alessia Leone, Gregory Alexander Raciti, Francesco Andreozzi, Michele Longo, Francesca Fiory, Francesco Beguinot, Claudia Miele
Methylglyoxal (MGO) is a reactive dicarbonyl produced as by-product of glycolysis, and its formation is heightened in hyperglycaemia. MGO plasma levels are two-fold to five-fold increased in diabetics and its accumulation promotes the progression of vascular complications. Impairment of endothelium-derived nitric oxide represents a common feature of endothelial dysfunction in diabetics. We previously demonstrated that MGO induces endothelial insulin resistance. Increasing evidence shows that high glucose and MGO modify vascular expression of several microRNAs (miRNAs), suggesting their potential role in the impairment of endothelial insulin sensitivity...
November 15, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27861144/inhibition-of-oxidative-phosphorylation-suppresses-the-development-of-osimertinib-resistance-in-a-preclinical-model-of-egfr-driven-lung-adenocarcinoma
#11
Matthew J Martin, Cath Eberlein, Molly Taylor, Susan Ashton, David Robinson, Darren Cross
Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis is often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) is a novel EGFR tyrosine kinase inhibitor (TKI) that is potent and selective for sensitising (EGFRm) and T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious in patients with EGFRm/ T790M advanced NSCLC who have progressed after EGFR-TKI treatment...
November 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27857979/normoxic-or-hypoxic-adaptation-in-response-to-antiangiogenic-therapy-clinical-implications
#12
M Quintela-Fandino
In a recent article in Cell Reports, we described a novel mechanism for acquired resistance against new small-molecule antiangiogenic tyrosine-kinase inhibitors (TKIs). Vascular normalization-inducing TKIs block glycolysis and trigger a nutritional stress response in the tumor compartment that induces a (targetable) switch to mitochondrial metabolism. We discuss the implications for clinical/translational studies and suggest areas for future research.
2016: Molecular & Cellular Oncology
https://www.readbyqxmd.com/read/27856430/glycolysis-and-oxidative-phosphorylation-are-essential-for-purinergic-receptor-mediated-angiogenic-responses-in-vasa-vasorum-endothelial-cells
#13
Martin Lapel, Philip Weston, Derek Strassheim, Vijaya Karoor, Nana Burns, Taras Lyubchenko, Petr Paucek, Kurt R Stenmark, Evgenia V Gerasimovskaya
Angiogenesis is an energy demanding process, however, the role of cellular energy pathways and their regulation by extracellular stimuli, especially extracellular nucleotides, remain largely unexplored. Using metabolic inhibitors of glycolysis (2-deoxyglucose, 2-DG) and oxidative phosphorylation (oligomycin, rotenone, and FCCP) we demonstrate that glycolysis and OXPHOS are both essential for angiogenic responses of vasa vasorum endothelial cell (VVEC). Treatment with P2R agonists, ATP and MeSADP, but not P1 receptor agonist, adenosine, increased glycolytic activity in VVEC (measured by extracellular acidification rate and lactate production)...
November 16, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27849558/identification-of-a-fluorescent-small-molecule-enhancer-for-therapeutic-autophagy-in-colorectal-cancer-by-targeting-mitochondrial-protein-translocase-tim44
#14
Yinghui Huang, Jie Zhou, Shenglin Luo, Yang Wang, Jintao He, Peng Luo, Zelin Chen, Tao Liu, Xu Tan, Juanjuan Ou, Hongming Miao, Houjie Liang, Chunmeng Shi
OBJECTIVE: As the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated. However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues. This study aims to develop a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism. DESIGN: A series of mitochondria-targeting near-infrared (NIR) fluorophores were synthesised, screened and identified for their autophagy-enhancing activity...
November 14, 2016: Gut
https://www.readbyqxmd.com/read/27846210/lactate-inhibits-the-pro-inflammatory-response-and-metabolic-reprogramming-in-murine-macrophages-in-a-gpr81-independent-manner
#15
Agustina Errea, Delphine Cayet, Philippe Marchetti, Cong Tang, Jerome Kluza, Stefan Offermanns, Jean-Claude Sirard, Martin Rumbo
Lactate is an essential component of carbon metabolism in mammals. Recently, lactate was shown to signal through the G protein coupled receptor 81 (GPR81) and to thus modulate inflammatory processes. This study demonstrates that lactate inhibits pro-inflammatory signaling in a GPR81-independent fashion. While lipopolysaccharide (LPS) triggered expression of IL-6 and IL-12 p40, and CD40 in bone marrow-derived macrophages, lactate was able to abrogate these responses in a dose dependent manner in Gpr81-/- cells as well as in wild type cells...
2016: PloS One
https://www.readbyqxmd.com/read/27845178/glutamate-dehydrogenase-as-a-neuroprotective-target-against-brain-ischemia-and-reperfusion
#16
A Young Kim, Kyeong-Hoon Jeong, Jae Ho Lee, Yup Kang, Soo Hwan Lee, Eun Joo Baik
Deregulation of glutamate homeostasis is associated with degenerative neurological disorders. Glutamate dehydrogenase (GDH) is important for glutamate metabolism and plays a central role in expanding the pool of tricarboxylic acid (TCA) cycle intermediate alpha-ketoglutarate (α-KG), which improves overall bioenergetics. Under high energy demand, maintenance of ATP production results in functionally active mitochondria. Here, we tested whether the modulation of GDH activity can rescue ischemia/reperfusion-induced neuronal death in an in vivo mouse model of middle artery occlusion and an in vitro oxygen/glucose depletion model...
November 12, 2016: Neuroscience
https://www.readbyqxmd.com/read/27836974/wzb117-inhibits-glut1-mediated-sugar-transport-by-binding-reversibly-at-the-exofacial-sugar-binding-site
#17
Ogooluwa A Ojelabi, Kenneth P Lloyd, Andrew H Simon, Julie K De Zutter, Anthony Carruthers
WZB117 (2-fluoro-6-(m-hydroxybenzoyloxy) phenyl m-hydroxybenzoate) inhibits passive sugar transport in human erythrocytes and cancer cell lines and, by limiting glycolysis, inhibits tumor growth in mice. This study explores how WZB117 inhibits the erythrocyte sugar transporter GLUT1 and examines the transporter isoform-specificity of inhibition. WZB117 reversibly and competitively inhibits erythrocyte 3-O-methylglucose (3MG) uptake with Ki(app) = 6 microM but is a noncompetitive inhibitor of sugar exit. Cytochalasin B (CB) is a reversible, noncompetitive inhibitor of 3MG uptake with Ki(app) = 0...
November 11, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27836699/the-mitochondria-targeted-imidazole-substituted-oleic-acid-tpp-ioa-affects-mitochondrial-bioenergetics-and-its-protective-efficacy-in-cells-is-influenced-by-cellular-dependence-on-aerobic-metabolism
#18
Lucas A Maddalena, Mikel Ghelfi, Jeffrey Atkinson, Jeffrey A Stuart
A variety of mitochondria-targeted small molecules have been invented to manipulate mitochondrial redox activities and improve function in certain disease states. 3-Hydroxypropyl-triphenylphosphonium-conjugated imidazole-substituted oleic acid (TPP-IOA) was developed as a specific inhibitor of cytochrome c peroxidase activity that inhibits apoptosis by preventing cardiolipin oxidation and cytochrome c release to the cytosol. Here we evaluate the effects of TPP-IOA on oxidative phosphorylation in isolated mitochondria and on mitochondrial function in live cells...
January 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27835826/reactive-oxygen-species-driven-hif1%C3%AE-triggers-accelerated-glycolysis-in-endothelial-cells-exposed-to-low-oxygen-tension
#19
Jin-Young Paik, Kyung-Ho Jung, Jin-Hee Lee, Jin-Won Park, Kyung-Han Lee
Endothelial cells and their metabolic state regulate glucose transport into underlying tissues. Here, we show that low oxygen tension stimulates human umbilical vein endothelial cell (18)F-fluorodeoxyglucose ((18)F-FDG) uptake and lactate production. This was accompanied by augmented hexokinase activity and membrane Glut-1, and increased accumulation of hypoxia-inducible factor-1α (HIF1α). Restoration of oxygen reversed the metabolic effect, but this was blocked by HIF1α stabilization. Hypoxia-stimulated (18)F-FDG uptake was completely abrogated by silencing of HIF1α expression or by a specific inhibitor...
October 26, 2016: Nuclear Medicine and Biology
https://www.readbyqxmd.com/read/27832958/hypoxia-inducible-factor-prolyl-4-hydroxylase-inhibition-in-cardiometabolic-diseases
#20
REVIEW
Peppi Koivunen, Raisa Serpi, Elitsa Y Dimova
Hypoxia-inducible factor prolyl 4-hydroxylases (HIF-P4Hs, also called PHDs and EglNs) are enzymes that act as cellular oxygen sensors. They are the main downregulators of the hypoxia-inducible factor (HIF). HIF-P4Hs can be targeted with small molecule inhibitors, which stabilize HIF under normoxia and initiate the hypoxia response. Such inhibitors are in phase 2 and 3 clinical trials for the treatment of anemia due to their ability to induce erythropoietin and iron metabolism genes. Recent data suggest that HIF-P4H inhibition has a therapeutic role beyond anemia in cardiac ischemia, obesity and metabolic dysfunction, and atherosclerosis...
November 8, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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