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Glycolysis inhibitors

Jillian E Milanes, Jimmy Suryadi, Jan Abendroth, Wesley C Van Voorhis, Kayleigh F Barrett, David M Dranow, Isabelle Q Phan, Stephen L Patrick, Soren D Rozema, Muhammad M Khalifa, Jennifer E Golden, James C Morris
Infection with the free-living amoeba Naegleria fowleri leads to life-threatening primary amoebic meningoencephalitis. Efficacious treatment options for these infections are limited and the mortality rate is very high (∼98%). 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...
February 19, 2019: Antimicrobial Agents and Chemotherapy
Phil Jun Kang, Jie Zheng, Gilju Lee, Daryeon Son, In-Yong Kim, Gwonhwa Song, Gyuman Park, Seungkwon You
Reprogramming of 'adult' differentiated somatic cells to 'embryonic' pluripotent stem cells accompanied by increased rate of glycolysis. Conversely, glycolysis triggers accumulation of advanced glycation end products (AGEs), a potential causative factor in aging, by promoting methylglyoxal production. Therefore, it is reasonable that pluripotent stem cells (PSCs) would specifically regulate glycolysis to maintain their embryonic features. In this study, we focused on glycine decarboxylase (GLDC), a key enzyme in the glycine cleavage system that regulates glycolysis and methylglyoxal production in cancer...
February 16, 2019: Metabolic Engineering
Yalei Yin, Mingju Sun, Xi Zhan, Changqing Wu, Pengyu Geng, Xiaoyan Sun, Yunsong Wu, Shuijun Zhang, Jianhua Qin, Zhengping Zhuang, Yang Liu
BACKGROUND: The bromodomain and extra-terminal domain (BET) inhibitor is a type of anti-tumor agent, currently being evaluated in phase I and II clinical trials for cancer therapy. It can decrease MYC expression levels and cause effective anti-tumor effects in diverse human cancers. However, its cytotoxic effect and related mechanisms of drug resistance are poorly understood in hepatocellular carcinomas (HCC). Here, we investigated the anti-tumor effects of BET inhibitor on HCC and the molecular mechanisms involved in its associated drug resistance...
February 15, 2019: Journal of Experimental & Clinical Cancer Research: CR
Yanyan Gao, Fang Yang, Xiu-An Yang, Li Zhang, Huixin Yu, Xian Cheng, Shichen Xu, Jie Pan, Kun Wang, Peifeng Li
BRAF V600E is the most common mutation identified in thyroid cancers. However, the relationship between BRAF V600E and metabolic reprogramming in thyroid cancer is unclear. Here, we investigate the mechanism of metabolic reprogramming in BRAF V600E thyroid cancer by constructing BRAF V600E-overexpressing and BRAF-knockdown thyroid cell lines for use in mitochondrial respiration and glycolysis experiments. Western blot and RT-qPCR were performed to measure the level of metabolism-related proteins, and various approaches were used to investigate transcriptional regulation...
February 15, 2019: FEBS Journal
Marah C Runtsch, Morgan C Nelson, Soh-Hyun Lee, Warren Voth, Margaret Alexander, Ruozhen Hu, Jared Wallace, Charisse Petersen, Vanja Panic, Claudio J Villanueva, Kimberley J Evason, Kaylyn M Bauer, Timothy Mosbruger, Sihem Boudina, Mary Bronner, June L Round, Micah J Drummond, Ryan M O'Connell
Identifying regulatory mechanisms that influence inflammation in metabolic tissues is critical for developing novel metabolic disease treatments. Here, we investigated the role of microRNA-146a (miR-146a) during diet-induced obesity in mice. miR-146a is reduced in obese and type 2 diabetic patients and our results reveal that miR-146a-/- mice fed a high-fat diet (HFD) have exaggerated weight gain, increased adiposity, hepatosteatosis, and dysregulated blood glucose levels compared to wild-type controls. Pro-inflammatory genes and NF-κB activation increase in miR-146a-/- mice, indicating a role for this miRNA in regulating inflammatory pathways...
February 15, 2019: PLoS Genetics
Chong Chen, Lipeng Bai, Fengqi Cao, Shengnan Wang, Huiwen He, Mingcheng Song, Huilin Chen, Yan Liu, Jian Guo, Qin Si, Yundi Pan, Ruizhe Zhu, Tsung-Hsien Chuang, Rong Xiang, Yunping Luo
The altered metabolism and acidic microenvironment plays an important role in promoting tumor malignant characteristics. A small population of cancer stem cells (CSCs) were considered as a therapy target to reserve tumor relapse, resistance, and metastasis. However, the molecular mechanism that regulates CSCs metabolism remains poorly understood. In this study, we demonstrate a fundamental role of stemness gene LIN28B in maintaining CSCs glycolysis metabolism. Using LIN28B-expressing cancer cell lines, we found that the rate of extracellular acidification, glucose uptake, and lactate secretion are all suppressed by LIN28B knockdown in vitro and in vivo...
February 11, 2019: Oncogene
Bin Liu, Wenjie Bai, Guoyao Ou, Jun Zhang
Cdh1 is a regulatory subunit of the anaphase promoting complex/cyclosome (APC/C), known to be involved in regulating neuronal survival. The role of Cdh1 in volatile anesthetics-induced neuronal apoptosis in the developing brain is unknown. In this study, we used postnatal day 7 (P7) and day 21 (P21) mice exposed to 2.3% sevoflurane for 6 h to investigate at which age and duration of exposure sevoflurane affects the expression of Cdh1 and glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and that of the pentose phosphate pathway (PPP) enzyme, Glucose-6-phosphate dehydrogenase (G6PD)...
February 11, 2019: ACS Chemical Neuroscience
Le Qian, Jie Zhang, Xiangguang Chen, Suzhen Qi, Peizhuo Wu, Chen Wang, Chengju Wang
Boscalid as one of the most widely used succinate dehydrogenase inhibitor (SDHI) fungicides has been frequently detected in both freshwater and estuarine environments. Its acute toxic effects on zebrafish and freshwater algae have been reported in our previous studies. To further investigate its chronic toxic effects to aquatic organisms, adult zebrafish were exposed for 28 days to a series of environmentally relevant boscalid concentrations in this study. Growth indicators and histopathology were determined in this study...
January 18, 2019: Environmental Pollution
Brock A Humphries, Johanna M Buschhaus, Yu-Chih Chen, Henry R Haley, Tonela Qyli, Benjamin Chiang, Nathan Shen, Shrila Rajendran, Alyssa Cutter, Yu-Heng Cheng, Yu-Ting Chen, Jason Cong, Phillip C Spinosa, Euisik Yoon, Kathryn E Luker, Gary D Luker
Migration and invasion of cancer cells constitute fundamental processes in tumor progression and metastasis. Migratory cancer cells commonly upregulate expression of plasminogen activator inhibitor 1 (PAI1), and PAI1 correlates with poor prognosis in breast cancer. However, mechanisms by which PAI1 promotes migration of cancer cells remain incompletely defined. Here we show that increased PAI1 drives rearrangement of the actin cytoskeleton, mitochondrial fragmentation, and glycolytic metabolism in triple negative breast cancer (TNBC) cells...
February 4, 2019: Molecular Cancer Research: MCR
Tiziana Vigo, Claudia La Rocca, Deriggio Faicchia, Claudio Procaccini, Maddalena Ruggieri, Marco Salvetti, Diego Centonze, Giuseppe Matarese, Antonio Uccelli
Administration of mesenchymal stem cells (MSC) ameliorate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), at both clinical and neuropathological levels. The therapeutic properties of MSC in EAE are mainly mediated by the modulation of pathogenic immune response, but other neurotropic effects, including decreased demyelination and axonal loss as well as promotion of tissue repair, play also a role. Properly controlled phase II clinical trials to explore the potential of MSC transplantation as a treatment for MS are underway...
January 28, 2019: Cell Death & Disease
Shaneice R Mitchell, Karilyn Larkin, Nicole R Grieselhuber, Tzung-Huei Lai, Matthew Cannon, Shelley Orwick, Pratibha Sharma, Yerdanose Asemelash, Pu Zhang, Virginia M Goettl, Larry Beaver, Alice Mims, Vinay K Puduvalli, James S Blachly, Amy Lehman, Bonnie Harrington, Sally Henderson, Justin T Breitbach, Katie E Williams, Shuai Dong, Erkan Baloglu, William Senapedis, Karl Kirschner, Deepa Sampath, Rosa Lapalombella, John C Byrd
Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities...
February 12, 2019: Blood Advances
Qiang Zhang, Yuan Qin, Jianmin Zhao, Yuanhao Tang, Xuejiao Hu, Weilong Zhong, Mimi Li, Shumin Zong, Meng Li, Honglian Tao, Zhen Zhang, Shuang Chen, Huijuan Liu, Lan Yang, Honggang Zhou, Yanrong Liu, Tao Sun, Cheng Yang
Tumor progression is dependent on metabolic reprogramming. Metastasis and vasculogenic mimicry (VM) are typical characteristics of tumor progression. The relationship among metastasis, VM, and metabolic reprogramming remains unclear. In this study, we identified the novel role of Twist1, a VM regulator, in the transcriptional regulation of thymidine phosphorylase (TP) expression. TP promoted the extracellular metabolism of thymidine into ATP and amino acids through the pentose Warburg effect by coupling the pentose phosphate pathway and glycolysis...
January 17, 2019: Cell Death & Disease
Andrew Wang, Scott D Pope, Jason S Weinstein, Shuang Yu, Cuiling Zhang, Carmen J Booth, Ruslan Medzhitov
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a highly mortal complication associated with sepsis. In adults, it is often seen in the setting of infections, especially viral infections, but the mechanisms that underlie pathogenesis are unknown. sHLH is characterized by a hyperinflammatory state and the presence hemophagocytosis. We found that sequential challenging of mice with a nonlethal dose of viral toll-like receptor (TLR) agonist followed by a nonlethal dose of TLR4 agonist, but not other permutations, produced a highly lethal state that recapitulates many aspects of human HLH...
January 23, 2019: Proceedings of the National Academy of Sciences of the United States of America
Guilan Zhu, Na Guo, Yanan Yong, Yawen Xiong, Qunyi Tong
2-Deoxy-D-glucose (2-DG) is a non-metabolizable glucose analogue and competitive inhibitor of glycolysis. Effect of 2-DG on gellan gum biosynthesis by Sphingomonas paucimobilis ATCC31461 were studied in this research. The concentration and the addition time of 2-DG significantly affected the biomass and gellan gum accumulation. The maximum gellan gum yield of 20.78 g/L was obtained with the addition of 50 µg/L of 2-DG at 24 h. The mechanism of 2-DG addition favoring to gellan production was revealed by determining the activities of key enzymes...
January 22, 2019: Bioprocess and Biosystems Engineering
Klaartje Somers, Victoria W Wen, Shiloh M C Middlemiss, Brenna Osborne, Helen Forgham, MoonSun Jung, Mawar Karsa, Molly Clifton, Angelika Bongers, Jixuan Gao, Chelsea Mayoh, Newsha Raoufi-Rad, Eric P Kusnadi, Kate M Hannan, David A Scott, Alan Kwek, Bing Liu, Claudia Flemming, Daria A Chudakova, Ruby Pandher, Tim W Failes, James Lim, Andrea Angeli, Andrei L Osterman, Toshihiko Imamura, Ursula R Kees, Claudiu T Supuran, Richard B Pearson, Ross D Hannan, Thomas P Davis, Joshua McCarroll, Maria Kavallaris, Nigel Turner, Andrei V Gudkov, Michelle Haber, Murray D Norris, Michelle J Henderson
Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment...
January 22, 2019: Oncogene
Arindam Banerjee, Charles N Birts, Matthew Darley, Rachel Parker, Alex H Mirnezami, Jonathan West, Ramsey I Cutress, Stephen A Beers, Matthew Jj Rose-Zerilli, Jeremy P Blaydes
Altered flux through major metabolic pathways is a hallmark of cancer cells and provides opportunities for therapy. Stem cell-like cancer (SCLC) cells can cause metastasis and therapy resistance. They possess metabolic plasticity, theoretically enabling resistance to therapies targeting a specific metabolic state. The C-terminal binding protein (CtBP) transcriptional regulators are potential therapeutic targets in highly glycolytic cancer cells, as they are activated by the glycolytic coenzyme nicotinamide adenine dinucleotide (NADH)...
January 22, 2019: Carcinogenesis
Qiyin Zhou, Hua Li, Yuanyuan Li, Mingjia Tan, Shaohua Fan, Cong Cao, Feilong Meng, Ling Zhu, Lili Zhao, Min-Xin Guan, Hongchuan Jin, Yi Sun
Abnormal activation of neddylation modification and dysregulated energy metabolism are frequently seen in many types of cancer cells. Whether and how neddylation modification affects cellular metabolism remains largely unknown. Here we showed that MLN4924, a small molecule inhibitor of neddylation modification, induces mitochondrial fission-to-fusion conversion in breast cancer cells via inhibiting ubiquitylation and degradation of fusion-promoting protein mitofusin (MFN1) by SCFβ-TrCP E3 ligase and blocking the mitochondrial translocation of fusion-inhibiting protein DRP1...
January 22, 2019: JCI Insight
Philippe Icard, Ludovic Fournel, Zherui Wu, Marco Alifano, Hubert Lincet
Cell cycle progression and division is regulated by checkpoint controls and sequential activation of cyclin-dependent kinases (CDKs). Understanding of how these events occur in synchrony with metabolic changes could have important therapeutic implications. For biosynthesis, cancer cells enhance glucose and glutamine consumption. Inactivation of pyruvate kinase M2 (PKM2) promotes transcription in G1 phase. Glutamine metabolism supports DNA replication in S phase and lipid synthesis in G2 phase. A boost in glycolysis and oxidative metabolism can temporarily furnish more ATP when necessary (G1/S transition, segregation of chromosomes)...
January 14, 2019: Trends in Biochemical Sciences
Zhenzhen Liu, Hongli Li, Lian He, Yu Xiang, Chengsen Tian, Can Li, Peng Tan, Ji Jing, Yanpin Tian, Lupei Du, Yun Huang, Leng Han, Minyong Li, Yubin Zhou
Glioblastoma (GBM) is among the most common and malignant types of primary brain tumors in adults, with a dismal prognosis. Although alkylating agents such as temozolomide are widely applied as the first-line treatment for GBM, they often cause chemoresistance and remain ineffective with recurrent GBM. Alternative therapeutics against GBM are urgently needed in the clinic. We report herein the discovery of a class of inhibitors (YZ129 and its derivatives) of the calcineurin-NFAT pathway that exhibited potent anti-tumor activity against GBM...
November 30, 2018: Cell Chemical Biology
Syam Nair, Kristina S Sobotka, Pooja Joshi, Pierre Gressens, Bobbi Fleiss, Claire Thornton, Carina Mallard, Henrik Hagberg
Accumulating evidence suggests that changes in the metabolic signature of microglia underlie their response to inflammation. We sought to increase our knowledge of how pro-inflammatory stimuli induce metabolic changes. Primary microglia exposed to lipopolysaccharide (LPS)-expressed excessive fission leading to more fragmented mitochondria than tubular mitochondria. LPS-mediated Toll-like receptor 4 (TLR4) activation also resulted in metabolic reprogramming from oxidative phosphorylation to glycolysis. Blockade of mitochondrial fission by Mdivi-1, a putative mitochondrial division inhibitor led to the reversal of the metabolic shift...
January 13, 2019: Glia
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