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Glycolysis inhibitors

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https://www.readbyqxmd.com/read/29353241/inhibition-of-endothelial-notch-signaling-impairs-fatty-acid-transport-and-leads-to-metabolic-and-vascular-remodeling-of-the-adult-heart
#1
Markus Jabs, Adam J Rose, Lorenz H Lehmann, Jacqueline Taylor, Iris Moll, Tjeerd P Sijmonsma, Stefanie E Herberich, Sven W Sauer, Gernot Poschet, Giuseppina Federico, Carolin Mogler, Eva-Maria Weis, Hellmut G Augustin, Minhong Yan, Norbert Gretz, Roland M Schmid, Ralf H Adams, Hermann-Joseph Gröne, Rüdiger Hell, Jürgen G Okun, Johannes Backs, Peter P Nawroth, Stephan Herzig, Andreas Fischer
Background -Nutrients are transported through endothelial cells before being metabolized in muscle cells. However, little is known about the regulation of endothelial transport processes. Notch signaling is a critical regulator of metabolism and angiogenesis during development. Here, we studied how genetic and pharmacological manipulation of endothelial Notch signaling in adult mice affects endothelial fatty acid transport, cardiac angiogenesis, and heart function. Methods -Endothelial-specific Notch inhibition was achieved by conditional genetic inactivation of Rbp-jκ in adult mice to analyze fatty acid metabolism and heart function...
January 20, 2018: Circulation
https://www.readbyqxmd.com/read/29352744/crystal-structure-of-adp-dependent-glucokinase-from-methanocaldococcus-jannaschii-in-complex-with-5-iodotubercidin-reveals-phosphoryl-transfer-mechanism
#2
Piotr Tokarz, Magdalena Wiśniewska, Marcin M Kamiński, Grzegorz Dubin, Przemysław Grudnik
ADP-dependent glucokinase (ADPGK) is an alternative novel glucose phosphorylating enzyme in a modified glycolysis pathway of hyperthermophilic Archaea. In contrast to classical ATP-dependent hexokinases, ADPGK utilizes ADP as a phosphoryl group donor. Here we present a crystal structure of archaeal ADPGK from Methanocaldococcus jannaschii in complex with an inhibitor, 5-iodotubercidin, D-glucose, inorganic phosphate and a magnesium ion. Detailed analysis of the architecture of the active site allowed for confirmation of the previously proposed phosphorylation mechanism and the crucial role of the invariant arginine residue (Arg197)...
January 20, 2018: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/29348439/dual-suppression-of-inner-and-outer-mitochondrial-membrane-functions-augments-apoptotic-responses-to-oncogenic-mapk-inhibition
#3
Madhavika N Serasinghe, Jesse D Gelles, Kent Li, Lauren Zhao, Franco Abbate, Marie Syku, Jarvier N Mohammed, Brateil Badal, Cuahutlehuanitzin A Rangel, Kyle L Hoehn, Julide Tok Celebi, Jerry Edward Chipuk
Mitogen-activated protein kinase (MAPK) pathway inhibitors show promise in treating melanoma, but are unsuccessful in achieving long-term remission. Concordant with clinical data, BRAFV600E melanoma cells eliminate glycolysis upon inhibition of BRAFV600E or MEK with the targeted therapies Vemurafenib or Trametinib, respectively. Consequently, exposure to these therapies reprograms cellular metabolism to increase mitochondrial respiration and restrain cell death commitment. As the inner mitochondrial membrane (IMM) is sub-organellar site of oxidative phosphorylation (OXPHOS), and the outer mitochondrial membrane (OMM) is the major site of anti-apoptotic BCL-2 protein function, we hypothesized that suppressing these critical mitochondrial membrane functions would be a rational approach to maximize the pro-apoptotic effect of MAPK inhibition...
January 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29343208/lapatinib-inhibits-breast-cancer-cell-proliferation-by-influencing-pkm2-expression
#4
Mingxiu Guan, Yingna Tong, Minghua Guan, Xiaobin Liu, Meng Wang, Ruifang Niu, Fei Zhang, Dong Dong, Jie Shao, Yunli Zhou
Pyruvate kinase type M2, which is expressed in multiple tumor cell types and plays a key role in aerobic glycolysis, also has nonglycolytic functions and can regulate transcription and cell proliferation. The results of this study show that epidermal growth factor receptor activation induces pyruvate kinase type M2 nuclear translocation. To further determine the relationship between pyruvate kinase type M2 and epidermal growth factor receptor, we analyzed pathological data from mammary glands and performed epidermal growth factor receptor/human epidermal growth factor receptor 2 knockdown to reveal that pyruvate kinase type M2 is associated with epidermal growth factor receptor and human epidermal growth factor receptor 2...
January 1, 2018: Technology in Cancer Research & Treatment
https://www.readbyqxmd.com/read/29337061/metabolic-reprogramming-in-keloid-fibroblasts-aerobic-glycolysis-and-a-novel-therapeutic-strategy
#5
Qi Li, Zelian Qin, Fangfei Nie, Hongsen Bi, Runlei Zhao, Bailin Pan, Jianxun Ma, Xiang Xie
Keloids, tumor-like fibroproliferative cutaneous lesions, were reported in metabolic disturbance. However, the metabolic character remains unclear. The purpose of this study is to determine if glycolytic reprogramming is important for the pathogenesis of keloids and to assess the inhibition potential of glycolysis in keloid treatment. An intracellular metabolic profile assay was used to compare metabolic phenotypes between normal skin fibroblasts and keloid fibroblasts (NFs and KFs). Our data indicated that KFs underwent reprogramming of their metabolic phonotype from oxidative phosphorylation to aerobic glycolysis (Warburg effect) with augmented glycolysis and glycolytic capacity...
January 11, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29336483/glucose-metabolism-during-in-vitro-maturation-of-mouse-oocytes-an-study-using-rna-interference
#6
Hong-Li Xie, Shuai Zhu, Jie Zhang, Jing Wen, Hong-Jie Yuan, Liu-Zhu Pan, Ming-Jiu Luo, Jing-He Tan
In previous studies on glucose metabolism during in vitro maturation, intact cumulus-oocyte complexes (COCs) were treated with enzyme inhibitors/activators. Because inhibitors/activators may have non-specificity and/or toxicity, and culture of COCs cannot differentiate whether glucose metabolism of cumulus cells (CCs) or that of the oocyte supports oocyte maturation, results from the previous studies must be verified by silencing genes in either CCs or cumulus-denuded oocytes (DOs). In this study, RNAi was adopted to specify the effects of glucose metabolism in CCs or DOs on oocyte maturation...
January 16, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29336479/inhibition-of-glycolytic-metabolism-in-glioblastoma-cells-by-pt3glc-combinated-with-pi3k-inhibitor-via-sirt3-mediated-mitochondrial-and-pi3k-akt-mapk-pathway
#7
Gang Wang, Xing-Li Fu, Jun-Jie Wang, Rui Guan, Yan Sun, Shing-Shun Tony To
Glioblastoma multiforme (GBM) is the most malignant and aggressive glioma with abnormal expression of genes that mediate glycolytic metabolism and tumor cell growth. Petunidin-3-O- glucoside (Pt3glc) is a kind of anthocyanin in the red grape and derived beverages, representing the most common naturally occurring anthocyanins with a reduced incidence of cancer and heart diseases. In this study, whether Pt3glc could effectively regulate glycolysis to inhibit GBM cell was investigated by using the DBTRG-05MG cell lines...
January 16, 2018: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/29333574/unique-metabolic-activation-of-adipose-tissue-macrophages-in-obesity-promotes-inflammatory-responses
#8
Lily Boutens, Guido J Hooiveld, Sourabh Dhingra, Robert A Cramer, Mihai G Netea, Rinke Stienstra
AIMS/HYPOTHESIS: Recent studies have identified intracellular metabolism as a fundamental determinant of macrophage function. In obesity, proinflammatory macrophages accumulate in adipose tissue and trigger chronic low-grade inflammation, that promotes the development of systemic insulin resistance, yet changes in their intracellular energy metabolism are currently unknown. We therefore set out to study metabolic signatures of adipose tissue macrophages (ATMs) in lean and obese conditions...
January 14, 2018: Diabetologia
https://www.readbyqxmd.com/read/29330287/targeted-akt-inhibition-in-prostate-cancer-cells-and-spheroids-reduces-aerobic-glycolysis-and-generation-of-hyperpolarized-1-13c-lactate
#9
Sui Seng Tee, Izabela Suster, Steven Truong, Sangmoo Jeong, Roozbeh Eskandari, Valentina Di Gialleonardo, Julio A Alvarez, Hannah N Aldeborgh, Kayvan Keshari
The PI3K/AKT/mTOR (PAM) signaling pathway is frequently mutated in prostate cancer. Specific AKT inhibitors are now in advanced clinical trials and this study investigates the effect of MK2206, a non-ATP competitive inhibitor, on the cellular metabolism in the context of prostate cancer. A significant reduction in cell motility and aerobic glycolysis was observed in prostate cancer cells with treatment. These changes were not accompanied by a reduction in the ratio of high-energy phosphates or a change in total protein levels of enzymes (e...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29317521/ca2-dependent-demethylation-of-phosphatase-pp2ac-promotes-glucose-deprivation-induced-cell-death-independently-of-inhibiting-glycolysis
#10
Ha Yin Lee, Yoko Itahana, Stefan Schuechner, Masahiro Fukuda, H Shawn Je, Egon Ogris, David M Virshup, Koji Itahana
Cancer cells increase glucose metabolism to support aerobic glycolysis. However, only some cancer cells are acutely sensitive to glucose withdrawal, and the underlying mechanism of this selective sensitivity is unclear. We showed that glucose deprivation initiates a cell death pathway in cancer cells that is dependent on the kinase RIPK1. Glucose withdrawal triggered rapid plasma membrane depolarization and an influx of extracellular calcium into the cell through the L-type calcium channel Cav1.3 (CACNA1D), followed by activation of the kinase CAMK1...
January 9, 2018: Science Signaling
https://www.readbyqxmd.com/read/29306210/anti-proliferative-effect-of-zea-mays-l-cob-extract-on-rat-c6-glioma-cells-through-regulation-of-glycolysis-mitochondrial-ros-and-apoptosis
#11
Eunmi Hwang, Sangwan Sim, Sang Hyuk Park, Ki Duk Song, Hak-Kyo Lee, Tae-Hwe Heo, Hyun Sik Jun, Sung-Jo Kim
Gliomas are one of the most common types of primary brain tumors, characterized by rapid proliferation and infiltration into normal brain tissue. Corncob is the most plentiful byproducts of Zea mays L., of which anti-cancer effect has not been reported. Therefore, we aimed to examine the anti-proliferative effect of a high-pressure hot-water extract of corncob on glioma cells and elucidated the underlying mechanism. The high-pressure hot-water corncob extract contained approximately 94.8 mg/g and 1.82 μg/g of total phenol and catechin, respectively...
January 3, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29305935/hedgehog-yap-signaling-pathway-regulates-glutaminolysis-to-control-hepatic-stellate-cell-activation
#12
Kuo Du, Jeongeun Hyun, Richard T Premont, Steve S Choi, Gregory A Michelotti, Marzena Swiderska-Syn, George D Dalton, Eric Thelen, Bahar Salimian Rizi, Youngmi Jung, Anna Mae Diehl
BACKGROUND & AIMS: Cirrhosis results from accumulation of myofibroblasts derived from quiescent hepatic stellate cells (Q-HSCs); it regresses when myofibroblastic HSCs are depleted. Hedgehog signaling promotes transdifferentiation of HSCs by activating Yes-associated protein 1 (YAP1 or YAP) and inducing aerobic glycolysis. However, increased aerobic glycolysis alone cannot meet the high metabolic demands of myofibroblastic HSCs. Determining the metabolic processes of these cells could lead to strategies to prevent progressive liver fibrosis, so we investigated whether glutaminolysis (conversion of glutamine to alpha-ketoglutarate) sustains energy metabolism and permits anabolism when Q-HSCs become myofibroblastic, and whether this is controlled by hedgehog signaling to YAP...
January 3, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29305912/new-natural-inhibitors-of-hexokinase-2-hk2-steroids-from-ganoderma-sinense
#13
Fengyan Bao, Kaiyin Yang, Canrong Wu, Suyu Gao, Penghe Wang, Lixia Chen, Hua Li
Hexokinase 2 (HK2), a rate-limiting enzyme in the first step of glycolysis pathway, expresses at high level in cancer cells compared with normal cells. HK2 provides a new target for cancer therapy due to its pivotal role in tumor tumourigenic and metastatic process. The structure-based virtual ligand screening in a small in-house database of natural products predicted that a new steroid, (22E,24R)-6β-methoxyergosta-7,9(11),22-triene-3β,5α-diol (2) from Ganoderma sinense has high binding affinity to HK2 with significant calculated binding free energy...
January 3, 2018: Fitoterapia
https://www.readbyqxmd.com/read/29299135/acquired-resistance-to-pi3k-mtor-inhibition-is-associated-with-mitochondrial-dna-mutation-and-glycolysis
#14
King Xin Koh, Gim Hwa Tan, Sarah Hong Hui Low, Mohd Feroz Mohd Omar, Min Ji Han, Barry Iacopetta, Ross Soo, Mounia Beloueche-Babari, Bhaskar Bhattacharya, Richie Soong
Acquired resistance (AQR) to drug treatment occurs frequently in cancer patients and remains an impediment to successful therapy. The aim of this study was to gain insight into how AQR arises following the application of PI3K/mTOR inhibitors. H1975 lung cancer cells with EGFR T790M mutations that confer resistance to EGFR inhibitors underwent prolonged treatment with the PI3K/mTOR inhibitor, BEZ235. Monoclonal cells with stable and increased resistance to BEZ235 were obtained after 8 months treatment. These AQR clones showed class-specific resistance to PI3K/mTOR inhibitors, reduced G1 cell cycle arrest and impedance of migration following PI3K/mTOR inhibition, reduced PTEN expression and increased Akt and S6RP phosphorylation...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29298131/a-systematic-review-of-p53-regulation-of-oxidative-stress-in-skeletal-muscle
#15
Kaitlyn Beyfuss, David A Hood
BACKGROUND: p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis. METHODS: A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases...
January 3, 2018: Redox Report: Communications in Free Radical Research
https://www.readbyqxmd.com/read/29286239/suppression-of-tumor-energy-supply-by-liposomal-nanoparticle-mediated-inhibition-of-aerobic-glycolysis
#16
Yinlong Zhang, JingYan Wei, Jiaqi Xu, Wei Sun Leong, Guangna Liu, Tianjiao Ji, Zhiqiang Cheng, Jing Wang, Jiayan Lang, Ying Zhao, Linhao You, Xiao Zhao, Taotao Wei, Greg J Anderson, Sheng Qi, Jing Kong, Guangjun Nie, Suping Li
Aerobic glycolysis enables cancer cells to rapidly take up nutrients (e.g., nucleotides, amino acids, lipids) and incorporate them into the biomass needed to produce a new cell. In contrast to existing chemotherapy/radiotherapy strategies, inhibiting aerobic glycolysis to limit ATP yield is a highly efficient approach for suppressing tumor cell proliferation. However, most, if not all, current inhibitors of aerobic glycolysis cause significant adverse effects, due to their nonspecific delivery and distribution to non-diseased organs, low bioavailability and a narrow therapeutic window...
December 29, 2017: ACS Applied Materials & Interfaces
https://www.readbyqxmd.com/read/29281667/urothelial-maxik-activity-regulates-mucosal-and-detrusor-metabolism
#17
Yi Wang, Gary G Deng, Kelvin P Davies
There is increasing evidence for a role of MaxiK potassium channel-activity in regulating the metabolism and intracellular signaling of non-contractile bladder mucosal tissues. At present however no studies have determined the impact of urothelial MaxiK-activity on overall bladder metabolism. To address this we have investigated the effect of bladder lumen instillation of the MaxiK inhibitor, iberiotoxin (IBTX), on mucosal and detrusor metabolism using metabolomics. Since IBTX does not cross plasma membranes, when instilled into the bladder lumen it would only effect urothelially expressed MaxiK-activity...
2017: PloS One
https://www.readbyqxmd.com/read/29247711/hexokinase-2-confers-resistance-to-cisplatin-in-ovarian-cancer-cells-by-enhancing-cisplatin-induced-autophagy
#18
Xiao-Yan Zhang, Meng Zhang, Qing Cong, Ming-Xing Zhang, Meng-Yu Zhang, Ying-Ying Lu, Cong-Jian Xu
The high mortality rate of ovarian cancer is connected with the development of acquired resistance to multiple cancer drugs, especially cisplatin. Activation of cytoprotective autophagy has been implicated as a contributing mechanism for acquired cisplatin resistance in ovarian cancer cells. Hexokinase 2 (HK2) phosphorylates glucose to generate glucose-6-phosphate, the rate-limiting step in glycolysis. Higher HK2 expression has been associated with chemoresistance in ovarian cancer. However, whether HK2 functionally contributes to cisplatin resistance in ovarian cancer is unclear...
December 13, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29246941/mitochondrial-inhibition-augments-the-efficacy-of-imatinib-by-resetting-the-metabolic-phenotype-of-gastrointestinal-stromal-tumor
#19
Gerardo A Vitiello, Benjamin D Medina, Shan Zeng, Timothy G Bowler, Jennifer Q Zhang, Jennifer K Loo, Nesteene J Param, Mengyuan Liu, John A Moral, Julia N Zhao, Ferdinand Rossi, Cristina R Antonescu, Vinod P Balachandran, Justin R Cross, Ronald P DeMatteo
PURPOSE: Imatinib dramatically reduces GIST 18 F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown. EXPERIMENTAL DESIGN: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered Kit V558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity...
December 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29245898/a-novel-small-molecule-arylsulfonamide-causes-energetic-stress-and-suppresses-breast-and-lung-tumor-growth-and-metastasis
#20
Xin Dai, Stefan Kaluz, Ying Jiang, Lei Shi, DeAngelo Mckinley, Yingzhe Wang, Binghe Wang, Erwin G Van Meir, Chalet Tan
Neoplastic cells display reprogrammed metabolism due to the heightened energetic demands and the need for biomass synthesis of a growing tumor. Targeting metabolic vulnerabilities is thus an important goal for cancer therapy. Here, we describe a novel small-molecule arylsulfonamide (N-cyclobutyl-N-((2,2-dimethyl-2H-pyrano[3,2-b]pyridin-6-yl)methyl)-3,4-dimethoxybenzenesulfonamide) that exerts potent cytotoxicity and energetic stress on tumor cells while largely sparing non-cancerous human cells. In tumor cells, it stimulates glycolysis and accelerates glucose consumption...
November 21, 2017: Oncotarget
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