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dichloroacetate

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https://www.readbyqxmd.com/read/29137417/inhibition-of-retinoic-acid-receptor-%C3%AE-signaling-confers-glycolytic-dependence-and-sensitization-to-dichloroacetate-in-melanoma-cells
#1
Cecilie Abildgaard, Christina Dahl, Ahmad Abdul-Al, Annette Christensen, Per Guldberg
Dysregulation of metabolism during melanoma progression is tightly associated with the acquisition of genetic and epigenetic alterations in regulators of metabolic pathways. Retinoic acid receptor beta (RARβ) is epigenetically silenced in a large proportion of melanomas, but a link between RARβ and metabolic rewiring of melanoma has not been established. Here, we show that in primary human melanocytes, all-trans retinoic acid (a RARβ agonist) induced growth inhibition accompanied by a decrease in both glycolytic and oxidative metabolism, whereas selective inhibition of RARβ led to an increase in the basal glycolytic rate and increased sensitivity to inhibition of glycolysis...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29129554/development-of-a-novel-observer-reported-outcome-tool-as-the-primary-efficacy-outcome-measure-for-a-rare-disease-randomized-controlled-trial
#2
Peter W Stacpoole, Jonathan Shuster, John L P Seamus Thompson, Sara Jo Nixon, Robert A Prather, Lee Ann Lawson, Baiming Zou, Richard Buchsbaum
We developed an Observer-Reported Outcome (ObsRO) survey instrument to be applied in a multicenter, placebo-controlled, crossover randomized controlled trial of dichloroacetate in children with pyruvate dehydrogenase complex deficiency. The instrument quantifies a subject's at-home level of functionality, as reported by a parent/caregiver, who were instrumental in providing the clinical descriptors and domains that formed the instrument's content. Feasibility testing of the ObsRO tool showed it to be easy to use and comprehensive in capturing the major clinical functional limitations of affected children and requires less than 5min for a parent/caregiver to complete daily...
November 9, 2017: Mitochondrion
https://www.readbyqxmd.com/read/29107351/drinking-water-disinfection-by-products-during-pregnancy-and-child-neuropsychological-development-in-the-inma-spanish-cohort-study
#3
Cristina M Villanueva, Esther Gracia-Lavedan, Jordi Julvez, Loreto Santa-Marina, Nerea Lertxundi, Jesús Ibarluzea, Sabrina Llop, Ferran Ballester, Ana Fernández-Somoano, Adonina Tardón, Martine Vrijheid, Mònica Guxens, Jordi Sunyer
BACKGROUND: Disinfection by-products (DBPs) constitute a complex mixture of prevalent chemicals in drinking water and there is evidence of neurotoxicity for some of them. OBJECTIVES: We evaluated the association between estimates of DBP exposure during pregnancy and child neuropsychological outcomes at 1 and 4-5years of age. METHODS: We conducted a population-based mother-child cohort study in Spain with recruitment at first trimester of gestation (INMA Project, 2003-2008)...
January 2018: Environment International
https://www.readbyqxmd.com/read/29093638/inhibition-of-hif1%C3%AE-and-pdk-induces-cell-death-of-glioblastoma-multiforme
#4
Jiwon Esther Han, Pyung Won Lim, Chul Min Na, You Sik Choi, Joo Young Lee, Yona Kim, Hyung Woo Park, Hyo Eun Moon, Man Seung Heo, Hye Ran Park, Dong Gyu Kim, Sun Ha Paek
Glioblastoma multiforme (GBM) is the most common and aggressive form of brain tumors. GBMs, like other tumors, rely relatively less on mitochondrial oxidative phosphorylation (OXPHOS) and utilize more aerobic glycolysis, and this metabolic shift becomes augmented under hypoxia. In the present study, we investigated the physiological significance of altered glucose metabolism and hypoxic adaptation in the GBM cell line U251 and two newly established primary GBMs (GBM28 and GBM37). We found that these three GBMs exhibited differential growth rates under hypoxia compared to those under normoxia...
October 2017: Experimental Neurobiology
https://www.readbyqxmd.com/read/29070699/inhibition-of-pyruvate-dehydrogenase-kinase-improves-pulmonary-arterial-hypertension-in-genetically-susceptible-patients
#5
Evangelos D Michelakis, Vikram Gurtu, Linda Webster, Gareth Barnes, Geoffrey Watson, Luke Howard, John Cupitt, Ian Paterson, Richard B Thompson, Kelvin Chow, Declan P O'Regan, Lan Zhao, John Wharton, David G Kiely, Adam Kinnaird, Aristeidis E Boukouris, Chris White, Jayan Nagendran, Darren H Freed, Stephen J Wort, J Simon R Gibbs, Martin R Wilkins
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation...
October 25, 2017: Science Translational Medicine
https://www.readbyqxmd.com/read/29059435/therapeutic-targeting-of-the-pyruvate-dehydrogenase-complex-pyruvate-dehydrogenase-kinase-pdc-pdk-axis-in-cancer
#6
REVIEW
Peter W Stacpoole
The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. Inhibition of PDC activity by pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation has been associated with the pathobiology of many disorders of metabolic integration, including cancer. Consequently, the PDC/PDK axis has long been a therapeutic target. The most common underlying mechanism accounting for PDC inhibition in these conditions is post-transcriptional upregulation of one or more PDK isoforms, leading to phosphorylation of the E1α subunit of PDC...
November 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/29024715/proposal-of-a-flow-scheme-for-the-chemical-form-based-quantitative-analysis-of-chlorine-compounds-in-pulp-for-sanitary-products-and-verification-of-safety
#7
Takeharu Wada, Kei Iwasaki, Yasushi Minobe, Mitsuhiro Wada, Shigeo Imai, Satoko Ishii
To determine the amounts and chemical forms of chlorine compounds in elemental chlorine-free (ECF) bleached pulp for sanitary products, a chemical-form-based quantitative analysis flow scheme was created. The scheme involves quantitative determination of compounds eluted in elution tests assuming dermal exposure. The results indicated that most of the chlorine compounds in pulp used for sanitary products were insoluble organically bound chlorine and water-soluble chlorides consisting of chloride ions. The total amount of chlorine obtained by analysis of the total chlorine in the pulp products was close to the sum of the amounts of water-soluble chlorides, residual chlorine, chloroacetic acids, and insoluble organically bound chlorine...
October 9, 2017: Regulatory Toxicology and Pharmacology: RTP
https://www.readbyqxmd.com/read/29023340/associations-between-disinfection-by-product-exposures-and-craniofacial-birth-defects
#8
John A Kaufman, J Michael Wright, Amanda Evans, Zorimar Rivera-Núñez, Amy Meyer, Michael G Narotsky
OBJECTIVE: Examine associations between craniofacial birth defects (CFDs) and disinfection by-product (DBP) exposures, including the sum of four trihalomethanes (THM4) and five haloacetic acids (HAA5) (i.e., DBP9). METHODS: We calculated first trimester adjusted odds ratios (aORs) for different DBPs in a matched case-control study of 366 CFD cases in Massachusetts towns with complete 1999-2004 THM and HAA data. RESULTS: We detected elevated aORs for cleft palate with DBP9 (highest quintile aOR = 3...
October 11, 2017: Journal of Occupational and Environmental Medicine
https://www.readbyqxmd.com/read/28964917/redox-imbalance-due-to-the-loss-of-mitochondrial-nad-p-transhydrogenase-markedly-aggravates-high-fat-diet-induced-fatty-liver-disease-in-mice
#9
Claudia D C Navarro, Tiago R Figueira, Annelise Francisco, Genoefa A Dal'Bó, Juliana A Ronchi, Juliana C Rovani, Cecilia A F Escanhoela, Helena C F Oliveira, Roger F Castilho, Anibal E Vercesi
The mechanisms by which a high fat diet (HFD) promotes non-alcoholic fatty liver disease (NAFLD) appear to involve liver mitochondrial dysfunctions and redox imbalance. We hypothesized that a HFD would increase mitochondrial reliance on NAD(P)-transhydrogenase (NNT) as the source of NADPH for antioxidant systems that counteract NAFLD development. Therefore, we studied HFD-induced liver mitochondrial dysfunctions and NAFLD in C57Unib.B6 congenic mice with (Nnt(+/+)) or without (Nnt(-/-)) NNT activity; the spontaneously mutated allele (Nnt(-/-)) was inherited from the C57BL/6J mouse substrain...
September 28, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28962523/metabolic-disruption-early-in-life-is-associated-with-latent-carcinogenic-activity-of-dichloroacetic-acid-in-mice
#10
Leah C Wehmas, Anthony B DeAngelo, Susan D Hester, Brian N Chorley, Gleta Carswell, Greg R Olson, Michael H George, Julia H Carter, Sandra R Eldridge, Anna Fisher, Beena Vallanat, Charles E Wood
Early-life environmental factors can influence later-life susceptibility to cancer. Recent evidence suggests that metabolic pathways may mediate this type of latency effect. Previously, we reported that short-term exposure to dichloroacetic acid (DCA) increased liver cancer in mice 84 weeks after exposure was stopped. Here, we evaluated time course dynamics for key events related to this effect. This study followed a stop-exposure design in which 28-day-old male B6C3F1 mice were given the following treatments in drinking water for up to 93 weeks: deionized water (dH2O, control); 3...
October 1, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28943110/therapies-for-mitochondrial-diseases-and-current-clinical-trials
#11
REVIEW
Ayman W El-Hattab, Ana Maria Zarante, Mohammed Almannai, Fernando Scaglia
Mitochondrial diseases are a clinically and genetically heterogeneous group of disorders that result from dysfunction of the mitochondrial oxidative phosphorylation due to molecular defects in genes encoding mitochondrial proteins. Despite the advances in molecular and biochemical methodologies leading to better understanding of the etiology and mechanism of these diseases, there are still no satisfactory therapies available for mitochondrial disorders. Treatment for mitochondrial diseases remains largely symptomatic and does not significantly alter the course of the disease...
September 18, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28934276/enhanced-pyruvate-dehydrogenase-activity-improves-cardiac-outcomes-in-a-murine-model-of-cardiac-arrest
#12
Lin Piao, Yong-Hu Fang, Manfred M Kubler, Michael W Donnino, Willard W Sharp
RATIONALE: Post-ischemic changes in cellular metabolism alter myocardial and neurological function. Pyruvate dehydrogenase (PDH), the limiting step in mitochondrial glucose oxidation, is inhibited by increased expression of PDH kinase (PDK) during ischemia/reperfusion injury. This results in decreased utilization of glucose to generate cellular ATP. Post-cardiac arrest (CA) hypothermia improves outcomes and alters metabolism, but its influence on PDH and PDK activity following CA are unknown...
2017: PloS One
https://www.readbyqxmd.com/read/28928817/dichloroacetate-induces-protective-autophagy-in-esophageal-squamous-carcinoma-cells
#13
Hong-Yu Jia, He-Nan Wang, Feng-Yu Xia, Yan Sun, Hong-Li Liu, Li-Li Yan, Shan-Shan Li, Dong-Chun Jiang, Mei-Mei Xu
Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase, which promotes the flux of carbohydrates into mitochondria and enhances the aerobic oxidation of glucose. DCA has previously been demonstrated to exhibit antitumor properties. The present study revealed that treatment with DCA induced increased levels of autophagy-associated proteins in esophageal squamous carcinoma cells while minimally affecting apoptosis. The present study examined the localization of light chain (LC)-3 by adenovirus infection with a green fluorescent protein (FP)-red FP-LC3 reporter construction and confirmed that DCA treatment induced significant autophagy...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28915065/targeting-hif-1%C3%AE-pdk1-axis-by-dichloroacetate-dca-suppresses-bleomycin-induced-pulmonary-fibrosis
#14
Justin Goodwin, Hyunsung Choi, Meng-Hsiung Hsieh, Michael L Neugent, Jung-Mo Ahn, Heather N Hayenga, Pankaj K Singh, David B Shackelford, In-Kyu Lee, Vladimir Shulaev, Shanta Dhar, Norihiko Takeda, Jung-Whan Kim
RATIONALE: Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences such as hypoxia contribute to their sustained activation and differentiation is poorly understood. OBJECTIVES: As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the pre-clinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis...
September 15, 2017: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/28914978/model-informed-dose-optimization-of-dichloroacetate-for-the-treatment-of-congenital-lactic-acidosis-in-children
#15
Naveen Mangal, Margaret O James, Peter W Stacpoole, Stephan Schmidt
Dichloroacetate (DCA) is an investigational drug used to treat congenital lactic acidosis and other mitochondrial disorders. Response to DCA therapy in young children may be suboptimal following body weight-based dosing. This is because of autoinhibition of its metabolism, age-dependent changes in pharmacokinetics, and polymorphisms in glutathione transferase zeta 1 (GSTZ1), its primary metabolizing enzyme. Our objective was to predict optimal DCA doses for the treatment of congenital lactic acidosis in children...
September 15, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28881758/suppression-of-pyruvate-dehydrogenase-kinase-2-re-sensitizes-paclitaxel-resistant-human-lung-cancer-cells-to-paclitaxel
#16
Hong Sun, Anyou Zhu, Xiang Zhou, Fengchao Wang
Despite impressive initial clinical responses, the majority of lung cancer patients treated with paclitaxel eventually develop resistance to the drug. Pyruvate dehydrogenase kinase-2 (PDK2) is a key regulator of glycolysis and oxidative phosphorylation, and its expression is increased in a variety of tumors. In this study, the role of PDK2 in mediating paclitaxel resistance in lung cancer cells was investigated using biochemical and isotopic tracing methods. Increased expression of PDK2 was observed in paclitaxel-resistant cells ascompared totheir parental cells...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881683/inhibition-of-cox2-enhances-the-chemosensitivity-of-dichloroacetate-in-cervical-cancer-cells
#17
Bo Li, Xinzhe Li, Haojun Xiong, Peng Zhou, Zhenhong Ni, Teng Yang, Yan Zhang, Yijun Zeng, Jintao He, Fan Yang, Nan Zhang, Yuting Wang, Yingru Zheng, Fengtian He
Dichloroacetate (DCA), a traditional mitochondria-targeting agent, has shown promising prospect as a sensitizer in fighting against malignancies including cervical cancer. But it is unclear about the effect of DCA alone on cervical tumor. Moreover, previous reports have demonstrated that the increased cyclooxygenase-2 (COX2) expression is associated with chemoresistance and poor prognosis of cervical cancer. However, it is still unknown whether COX2 can affect the sensitivity of DCA in cervical cancer cells...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28881665/hpv-associated-differential-regulation-of-tumor-metabolism-in-oropharyngeal-head-and-neck-cancer
#18
Young-Suk Jung, Abdo J Najy, Wei Huang, Seema Sethi, Michael Snyder, Wael Sakr, Gregory Dyson, Maik Hüttemann, Icksoo Lee, Rouba Ali-Fehmi, Silvia Franceschi, Linda Struijk, Harold E Kim, Ikuko Kato, Hyeong-Reh Choi Kim
HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption...
August 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28878225/the-pdk1-inhibitor-dichloroacetate-controls-cholesterol-homeostasis-through-the-erk5-mef2-pathway
#19
Abrar Ul Haq Khan, Nerea Allende-Vega, Delphine Gitenay, Sabine Gerbal-Chaloin, Claire Gondeau, Dang-Nghiem Vo, Sana Belkahla, Stefania Orecchioni, Giovanna Talarico, Francesco Bertolini, Milica Bozic, Jose M Valdivielso, Fabienne Bejjani, Isabelle Jariel, Isabel C Lopez-Mejia, Lluis Fajas, Charles-Henri Lecellier, Javier Hernandez, Martine Daujat, Martin Villalba
Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28870456/pharmacological-synergism-of-2-2-dichloroacetophenone-and-egfr-tki-to-overcome-tki-induced-resistance-in-nsclc-cells
#20
Zheng Yang, Xiaohui Hu, Shaolin Zhang, Wen Zhang, Kin Yip Tam
Combination treatment has been used as one of the therapeutic approaches for patients suffering from lung cancer, either to cope with the issue of acquired drug resistance due to prolong the use of a particular EGFR-TKi treatment, or to decrease the doses of each compound in order to reduce potential toxicity. 2,2-dichloroacetophenone (DAP) was reported as a PDK inhibitor recently, which is much more potent than dichloroacetate (DCA) in anti-cancer therapy. In this study, we applied DAP in combined with EGFR-TKis, erlotinib or gefitinib in NSCLC cell lines and NSCLC xenograft model...
November 15, 2017: European Journal of Pharmacology
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