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Glycolysis inhibitors

Yoko Tabe, Kaori Saitoh, Haeun Yang, Kazumasa Sekihara, Kotoko Yamatani, Vivian Ruvolo, Hikari Taka, Naoko Kaga, Mika Kikkawa, Hajime Arai, Takashi Miida, Michael Andreeff, Paul A Spagnuolo, Marina Konopleva
Adipocytes are the prevalent stromal cell type in adult bone marrow (BM), and leukemia cells continuously adapt to deficiency of nutrients acquiring chemoresistant profiles in the BM microenvironment. We have previously shown that fatty acid metabolism is a key energy pathway for survival of acute myeloid leukemia (AML) cells in the adipocyte-abundant BM microenvironment. The novel fatty acid β-oxidation (FAO) inhibitor avocatin B, an odd-numbered carbon lipid derived from the avocado fruit, induced apoptosis and growth inhibition in mono-cultured AML cells...
November 15, 2018: Scientific Reports
Jan Snášel, Iva Pichová
Mycobacterium tuberculosis (Mtb) causes both acute tuberculosis and latent, symptom-free infection that affects roughly one-third of the world's population. It is a globally important pathogen that poses multiple dangers. Mtb reprograms its metabolism in response to the host niche, and this adaptation contributes to its pathogenicity. Knowledge of the metabolic regulation mechanisms in Mtb is still limited. Pyruvate kinase, involved in the late stage of glycolysis, helps link various metabolic routes together...
November 9, 2018: Biochimica et biophysica acta. Proteins and proteomics
Jan Ježek, Lydie Plecitá-Hlavatá, Petr Ježek
Human hepatocellular carcinoma HepG2 cells are forced to oxidative phosphorylation (OXPHOS), when cultured in aglycemic conditions at galactose and glutamine. These Oxphos cells represent a prototype of cancer cell bioenergetics with mixed aerobic glycolysis and OXPHOS. We aimed to determine fractions of (i) glutaminolytic pathway involving aminotransferase reaction supplying 2-oxoglutarate (2OG) to the Krebs cycle vs. (ii) active segment of the Krebs cycle with aconitase and isocitrate dehydrogenase-3 (ACO-IDH3), which is typically inactive in cancer cells due to the citrate export from mitochondria...
2018: Frontiers in Endocrinology
Qian Zhang, Mingyan Shao, Xuefeng Zhang, Qiyan Wang, Dongqing Guo, Xiaomin Yang, Chun Li, Yong Wang
Aim: Danqi Pill (DQP), a Chinese medicine frequently prescribed in China, has been approved to improve cardiac function by regulating cardiac energy metabolism in heart failure (HF) after acute myocardial infarction (AMI) patients. The aim of this study was to explore whether the mechanism of DQP is associated to the lipid and glucose metabolism mediated via PPARγ (peroxisome proliferator-activated receptor gamma) pathway both in vivo and in vitro . Materials and Methods: Model of HF after AMI was established with ligation of left anterior descending artery on Sprague-Dawley (SD) rats...
2018: Frontiers in Pharmacology
Lingfan Xu, Enze Ma, Tao Zeng, Ruya Zhao, Yulei Tao, Xufeng Chen, Jeff Groth, Chaozhao Liang, Hailiang Hu, Jiaoti Huang
ATM is a well-known master regulator of double strand break (DSB) DNA repair and the defective DNA repair has been therapeutically exploited to develop PARP inhibitors based on the synthetic lethality strategy. ATM mutation is found with increased prevalence in advanced metastatic castration-resistant prostate cancer (mCRPC). However, the molecular mechanisms underlying ATM mutation-driving disease progression are still largely unknown. Here, we report that ATM mutation contributes to the CRPC progression through a metabolic rather than DNA repair mechanism...
January 1, 2019: Endocrine-related Cancer
Hongchao Li, Qinghua Liang, Lin Wang
Glioblastoma (GBM) is a common and aggressive brain tumor that is associated with significant increase in glycolysis for energy production. Icaritin is a natural compound and exhibits anticancer activity in GBM. However, the effect of icaritin on glycolysis in GBM cells remains unclear. The aim of the current study was to investigate the effect of icaritin on glycolysis in GBM cells. The human GBM cell lines U87 and T98G were treated with icaritin or the inhibitor of Stat3 (S3I-201) in the presence or absence of recombinant human interleukin (IL)-6...
November 2, 2018: Journal of Cellular Biochemistry
Guopeng Miao, Juan Han, Jifeng Zhang, Yihai Wu, Guanhe Tong
Pachymic acid (PA), a triterpenoid from Poria cocos, has various pharmacological effects, including anti-inflammatory, anti-cancer, anti-aging, and insulin-like properties. PA has gained considerable research attention, but the mechanism of its anti-cancer effects remains unclear. In this study, pyruvate kinase M2 (PKM2) was discovered as a PA target via the drug affinity responsive target stability. Molecular docking and enzyme assay revealed that PA is a competing activator of PKM2, and mimics the natural activator, fructose-1,6-bisphosphate...
October 30, 2018: Biological & Pharmaceutical Bulletin
Polina Maximchik, Alibek Abdrakhmanov, Evgeniya Inozemtseva, Pyotr A Tyurin-Kuzmin, Boris Zhivotovsky, Vladimir Gogvadze
The dependence of tumors on glycolysis for ATP generation offers a rationale for therapeutic strategies aimed at selective inhibition of the glycolytic pathway. Analysis of tumor cell responses to anticancer drugs revealed that inhibition of glycolysis by 2-deoxyglucose (2-DG) generally augmented the apoptotic response; however, in HCT116 human colon carcinoma cells, apoptosis was suppressed. A comparison of neuroblastoma SK-N-BE(2) and HCT116 cells revealed, that in contrast to HCT116, in SK-N-BE(2) cells 2-DG alone was able to induce cell death...
October 30, 2018: FEBS Journal
Karis A Ederer, Kelly Jin, Sarah Bouslog, Lu Wang, Gregory S Gorman, Glenn C Rowe, Peter Abadir, Daniel Raftery, Douglas Moellering, Daniel Promislow, Patricia Jumbo-Lucioni, Maria De Luca
The angiotensin-converting enzyme (ACE) is a peptidase that is involved in the synthesis of Angiotensin II, the bioactive component of the renin-angiotensin system. A growing body of literature argues for a beneficial impact of ACE inhibitors (ACEi) on age-associated metabolic disorders, mediated by cellular changes in reactive oxygen species (ROS) that improve mitochondrial function. Yet, our understanding of the relationship between ACEi therapy and metabolic parameters is limited. Here, we used three genetically diverse strains of Drosophila melanogaster to show that Lisinopril treatment reduces thoracic ROS levels and mitochondrial respiration in young flies, and increases mitochondrial content in middle-aged flies...
October 26, 2018: International Journal of Molecular Sciences
Luca Di Leo, Rolando Vegliante, Fabio Ciccarone, Illari Salvatori, Manuel Scimeca, Elena Bonanno, Andrea Sagnotta, Gian Luca Grazi, Katia Aquilano, Maria Rosa Ciriolo
Metabolic reprogramming is a typical feature of cancer cells aimed at sustaining high-energetic demand and proliferation rate. Here, we report clear-cut evidence for decreased expression of the adipose triglyceride lipase (ATGL), the first and rate-limiting enzyme of triglyceride hydrolysis, in both human and mouse-induced hepatocellular carcinoma (HCC). We identified metabolic rewiring as major outcome of ATGL overexpression in HCC-derived cell lines. Indeed, ATGL slackened both glucose uptake/utilization and cell proliferation in parallel with increased oxidative metabolism of fatty acids and enhanced mitochondria capacity...
October 26, 2018: Oncogene
Gang Wang, Jun-Jie Wang, Rui Guan, Yan Sun, Feng Shi, Jing Gao, Xing-Li Fu
Colorectal cancer is a heterogeneous group of diseases that result from the accumulation of different sets of genomic alterations, together with epigenomic alterations, and it is influenced by tumor-host interactions, leading to tumor cell growth and glycolytic imbalances. This review summarizes recent findings that involve multiple signaling molecules and downstream genes in the dysregulated glycolytic pathway. This paper further discusses the role of the dysregulated glycolytic pathway in the tumor initiation, progression and the concomitant systemic immunosuppression commonly observed in colorectal cancer patients...
October 15, 2018: Current Cancer Drug Targets
Yu Deng, Hong Li, Xinyi Yin, Hongbing Liu, Jing Liu, Dongjie Guo, Zheng Shi
BACKGROUND Recent studies have illustrated that the transcription co-repressor, C-terminal binding protein 1 (CtBP1), links the metabolic alterations to transcription controls in proliferation, EMT, genome stability, metabolism, and lifespan, but whether CtBP1 affects the cellular redox homeostasis is unexplored. This study was designed to investigate the mechanism of CtBP1-mediated transcription repression that contributes to the metabolic reprogramming. MATERIAL AND METHODS Knockdown of CtBP1 in both mouse MEF cells and human melanoma cells changed cell redox homeostasis...
October 25, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
Silvia Laura Locatelli, Giuseppa Careddu, Simone Serio, Francesca Maria Consonni, Akihiro Maeda, Srikant Viswanadha, Swaroop Vakkalanka, Luca Castagna, Armando Santoro, Paola Allavena, Antonio Sica, Carmelo Carlo-Stella
PURPOSE: Tumor-associated macrophages (TAMs) and the hyperactivation of phosphoinositide 3-kinase(PI3K)/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma (HL) and affect disease outcome. Since the δ and γ isoforms of PI3K are overexpressed in Hodgkin/Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kδ/γ inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response. EXPERIMENTAL DESIGN: HL cell lines (L-540, KM-H2 and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in HL cell line xenografts...
October 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Wen Zhang, Xiaohui Hu, Harapriya Chakravarty, Zheng Yang, Kin Yip Tam
Warburg effect, a preference of aerobic glycolysis for energy production even in the presence of adequate oxygen, is one of the most prominent distinctions of cancer cells from their normal equivalents. Upregulated pyruvate dehydrogenase kinase 1 (PDK1) was found to dominate the pivotal switch from mitochondrial respiration to aerobic glycolysis by inactivating pyruvate dehydrogenase (PDH) in cancer cells. PDK1 inhibition may lead to an unfavorable environment for cancer cells, which presents an opportunity for anticancer therapy...
October 16, 2018: ACS Combinatorial Science
Yong Wu, Yu Deng, Jun Zhu, Yachen Duan, WeiWei Weng, Xiaohua Wu
Background: Ovarian cancer (OC) is the leading cause of death among women with gynecologic malignancies. Recent studies have highlighted the role of Pim1, which belongs to a group of constitutively activated serine/threonine kinases, in cancer development. However, the effect of Pim1 in OC is largely unclear. Methods: OC cell lines with Pim1 overexpression or knockdown were constructed with len-tivirus transduction. Cell Counting Kit-8, colony formation, glycolysis stress test and in vivo mice models were carried out to assess the effect of Pim1 on OC biological functions...
2018: OncoTargets and Therapy
Shanshan Cui, Xi Yang, Lihong Zhang, Yi Zhao, Weiqun Yan
Researchers have shown that long noncoding RNAs (lncRNAs) are closely associated with the pathogenesis of colorectal cancer (CRC). In here, we aimed to explore the function of lncRNA MAFG-AS1 in tumorigenesis of CRC. Firstly, we found that the expression of MAFG-AS1 was upregulated in CRC tissues and positively correlated with the advanced tumor stage. A reciprocal repression was found between MAFG-AS1 and miR-147b. The expression of miR-147b was downregulated in CRC tissues and inversely correlated with MAFG-AS1...
October 19, 2018: Biochemical and Biophysical Research Communications
Cecilia Nigro, Alessia Leone, Michele Longo, Immacolata Prevenzano, Thomas H Fleming, Antonella Nicolò, Luca Parrillo, Rosa Spinelli, Pietro Formisano, Peter P Nawroth, Francesco Beguinot, Claudia Miele
Impaired angiogenesis leads to long-term complications and is a major contributor of the high morbidity in patients with Diabetes Mellitus (DM). Methylglyoxal (MGO) is a glycolysis byproduct that accumulates in DM and is detoxified by the Glyoxalase 1 (Glo1). Several studies suggest that MGO contributes to vascular complications through mechanisms that remain to be elucidated. In this study we have clarified for the first time the molecular mechanism involved in the impairment of angiogenesis induced by MGO accumulation...
October 18, 2018: Biochimica et biophysica acta. Molecular basis of disease
Benjamin Even, Sarah Fayad-Kobeissi, Jean-Marie Gagliolo, Roberto Motterlini, Jorge Boczkowski, Roberta Foresti, Maylis Dagouassat
Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by an irreversible proliferation arrest associated with secretion of inflammatory mediators. ROS production, known to induce senescence, is increased in COPD fibroblasts and mitochondria dysfunction participates in this process. Among the battery of cellular responses against oxidative stress damage, heme oxygenase (HO)-1 plays a critical role in defending the lung against oxidative stress and inflammation...
October 19, 2018: Aging Cell
Youming Zhang, Saffron A G Willis-Owen, Sarah Spiegel, Clare M Lloyd, Miriam F Moffatt, William O C M Cookson
RATIONALE: Polymorphisms on chromosome 17q21 confer the major genetic susceptibility to childhood-onset asthma. Risk alleles positively correlate with ORMDL3 expression. The locus influences disease severity and the frequency of human rhinovirus (HRV) initiated exacerbations. ORMDL3 is known to regulate sphingolipid synthesis by binding serine palmitoyltransferase (SPT), but its role in inflammation is incompletely understood. OBJECTIVES: To investigate the role of ORMDL3 in cellular inflammation...
October 19, 2018: American Journal of Respiratory and Critical Care Medicine
Shilpak Chatterjee, Paramita Chakraborty, Anusara Daenthanasanmak, Supinya Iamsawat, Gabriela Andrejeva, Libia A Luevano, Melissa M Wolf, Uday K Baliga, Carsten Krieg, Craig Beeson, Meenal Mehrotra, Elizabeth G Hill, Jeffrey C Rathmell, Xue-Zhong Yu, Andrew S Kraft, Shikhar Mehrotra
PURPOSE: Adoptive T cell therapy (ACT) of cancer, which involves the infusion of ex vivo engineered tumor epitope reactive autologous T cells into the tumor-bearing host, is a potential treatment modality for cancer. However, the durable anti-tumor response following ACT is hampered either by loss of effector function or survival of the anti-tumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the anti-tumor T cells are of immense importance...
October 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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