Imperial College London

DrHectorKeun

Faculty of MedicineDepartment of Surgery & Cancer

Reader in Metabolic Biochemistry
 
 
 
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Contact

 

+44 (0)20 7594 3161h.keun

 
 
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Location

 

officesInstitute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

129 results found

Chatziioannou A, Georgiadis P, Hebels DG, Liampa I, Valavanis I, Bergdahl IA, Johansson A, Palli D, Chadeau-Hyam M, Siskos AP, Keun H, Botsivali M, de Kok TMCM, Perez AE, Kleinjans JCS, Vineis P, Kyrtopoulos SAet al., 2017, Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

JOURNAL ARTICLE

Chaudhari U, Ellis JK, Wagh V, Nemade H, Hescheler J, Keun HC, Sachinidis Aet al., 2017, Metabolite signatures of doxorubicin induced toxicity in human induced pluripotent stem cell-derived cardiomyocytes., Amino Acids

Drug-induced off-target cardiotoxicity, particularly following anti-cancer therapy, is a major concern in new drug discovery and development. To ensure patient safety and efficient pharmaceutical drug development, there is an urgent need to develop more predictive cell model systems and distinct toxicity signatures. In this study, we applied our previously proposed repeated exposure toxicity methodology and performed (1)H NMR spectroscopy-based extracellular metabolic profiling in culture medium of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to doxorubicin (DOX), an anti-cancer agent. Single exposure to DOX did not show alteration in the basal level of extracellular metabolites while repeated exposure to DOX caused reduction in the utilization of pyruvate and acetate, and accumulation of formate compared to control culture medium. During drug washout, only pyruvate showed reversible effect and restored its utilization by hiPSC-CMs. On the other hand, formate and acetate showed irreversible effect in response to DOX exposure. DOX repeated exposure increased release of lactate dehydrogenase (LDH) in culture medium suggesting cytotoxicity events, while declined ATP levels in hiPSC-CMs. Our data suggests DOX perturbed mitochondrial metabolism in hiPSC-CMs. Pyruvate, acetate and formate can be used as metabolite signatures of DOX induced cardiotoxicity. Moreover, the hiPSC-CMs model system coupled with metabolomics technology offers a novel and powerful approach to strengthen cardiac safety assessment during new drug discovery and development.

JOURNAL ARTICLE

Itkonen HM, Brown M, Urbanucci A, Tredwell G, Lau CH, Barfeld S, Hart C, Guldvik IJ, Takhar M, Heemers HV, Erho N, Bloch K, Davicioni E, Derua R, Waelkens E, Mohler JL, Clarke N, Swinnen JV, Keun HC, Rekvig OP, Mills IGet al., 2017, Lipid degradation promotes prostate cancer cell survival, ONCOTARGET, Vol: 8, Pages: 38264-38275, ISSN: 1949-2553

JOURNAL ARTICLE

Kuepfer L, Clayton O, Thiel C, Cordes H, Nudischer R, Blank LM, Baier V, Heymans S, Caiment F, Roth A, Fluri DA, Kelm JM, Castell J, Selevsek N, Schlapbach R, Keun H, Hynes J, Sarkans U, Gmuender H, Herwig R, Niederer S, Schuchhardt J, Segall M, Kleinjans Jet al., 2017, A model-based assay design to reproduce in vivo patterns of acute drug-induced toxicity., Arch Toxicol

JOURNAL ARTICLE

Lau C-HE, Tredwell GD, Ellis JK, Lam EW-F, Keun HCet al., 2017, Metabolomic characterisation of the effects of oncogenic PIK3CA transformation in a breast epithelial cell line, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

JOURNAL ARTICLE

Maitre L, Lau C-HE, Vizcaino E, Robinson O, Casas M, Siskos AP, Want EJ, Athersuch T, Slama R, Vrijheid M, Keun HC, Coen Met al., 2017, Assessment of metabolic phenotypic variability in children's urine using H-1 NMR spectroscopy, SCIENTIFIC REPORTS, Vol: 7, ISSN: 2045-2322

JOURNAL ARTICLE

Siskos AP, Jain P, Romisch-Margl W, Bennet M, Achaintre D, Asad Y, Marney L, Richardson L, Koulman A, Griffin JL, Raynaud F, Scalbert A, Adamski J, Prehn C, Keun HCet al., 2017, Interlaboratory Reproducibility of a Targeted Metabolomics Platform for Analysis of Human Serum and Plasma, ANALYTICAL CHEMISTRY, Vol: 89, Pages: 656-665, ISSN: 0003-2700

JOURNAL ARTICLE

Sood D, Johnson N, Jain P, Siskos AP, Bennett M, Gilham C, Busana MC, Peto J, dos-Santos-Silva I, Keun HC, Fletcher Oet al., 2017, CYP3A7*1C allele is associated with reduced levels of 2-hydroxylation pathway oestrogen metabolites, BRITISH JOURNAL OF CANCER, Vol: 116, Pages: 382-388, ISSN: 0007-0920

JOURNAL ARTICLE

Valbuena GN, Tortarolo M, Bendotti C, Cantoni L, Keun HCet al., 2017, Altered Metabolic Profiles Associate with Toxicity in SOD1(G93A) Astrocyte-Neuron Co-Cultures., Sci Rep, Vol: 7

Non-cell autonomous processes involving astrocytes have been shown to contribute to motor neuron degeneration in amyotrophic lateral sclerosis. Mutant superoxide dismutase 1 (SOD1(G93A)) expression in astrocytes is selectively toxic to motor neurons in co-culture, even when mutant protein is expressed only in astrocytes and not in neurons. To examine metabolic changes in astrocyte-spinal neuron co-cultures, we carried out metabolomic analysis by (1)H NMR spectroscopy of media from astrocyte-spinal neuron co-cultures and astrocyte-only cultures. We observed increased glucose uptake with SOD1(G93A) expression in all co-cultures, but while co-cultures with only SOD1(G93A) neurons had lower extracellular lactate, those with only SOD1(G93A) astrocytes exhibited the reverse. Reduced branched-chain amino acid uptake and increased accumulation of 3-methyl-2-oxovalerate were observed in co-culture with only SOD1(G93A) neurons while glutamate was reduced in all co-cultures expressing SOD1(G93A). The shifts in these coupled processes suggest a potential block in glutamate processing that may impact motor neuron survival. We also observed metabolic alterations which may relate to oxidative stress responses. Overall, the different metabolite changes observed with the two SOD1(G93A) cell types highlight the role of the astrocyte-motor neuron interaction in the resulting metabolic phenotype, requiring further examination of altered met abolic pathways and their impact on motor neuron survival.

JOURNAL ARTICLE

Chaudhari U, Nemade H, Wagh V, Gaspar JA, Ellis JK, Srinivasan SP, Spitkovski D, Nguemo F, Louisse J, Bremer S, Hescheler J, Keun HC, Hengstler JG, Sachinidis Aet al., 2016, Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment, ARCHIVES OF TOXICOLOGY, Vol: 90, Pages: 2763-2777, ISSN: 0340-5761

JOURNAL ARTICLE

Fernando RN, Chaudhari U, Escher SE, Hengstler JG, Hescheler J, Jennings P, Keun HC, Kleinjans JCS, Kolde R, Kollipara L, Kopp-Schneider A, Limonciel A, Nemade H, Nguemo F, Peterson H, Prieto P, Rodrigues RM, Sachinidis A, Schaefer C, Sickmann A, Spitkovsky D, Stoeber R, van Breda SGJ, van de Water B, Vivier M, Zahedi RP, Vinken M, Rogiers Vet al., 2016, "Watching the Detectives" report of the general assembly of the EU project DETECTIVE Brussels, 24-25 November 2015, ARCHIVES OF TOXICOLOGY, Vol: 90, Pages: 1529-1539, ISSN: 0340-5761

JOURNAL ARTICLE

Koufaris C, Gallage S, Yang T, Lau C-H, Valbuena GN, Keun HCet al., 2016, Suppression of MTHFD2 in MCF-7 Breast Cancer Cells Increases Glycolysis, Dependency on Exogenous Glycine, and Sensitivity to Folate Depletion, JOURNAL OF PROTEOME RESEARCH, Vol: 15, Pages: 2618-2625, ISSN: 1535-3893

JOURNAL ARTICLE

Koufaris C, Valbuena GN, Pomyen Y, Tredwell GD, Nevedomskaya E, Lau C-H, Yang T, Benito A, Ellis JK, Keun HCet al., 2016, Systematic integration of molecular profiles identifies miR-22 as a regulator of lipid and folate metabolism in breast cancer cells., Oncogene, Vol: 35, Pages: 2766-2776

Dysregulated microRNA (miRNA) mediate malignant phenotypes, including metabolic reprogramming. By performing an integrative analysis of miRNA and metabolome data for the NCI-60 cell line panel, we identified an miRNA cluster strongly associated with both c-Myc expression and global metabolic variation. Within this cluster the cancer-associated and cardioprotective miR-22 was shown to repress fatty acid synthesis and elongation in tumour cells by targeting ATP citrate lyase and fatty acid elongase 6, as well as impairing mitochondrial one-carbon metabolism by suppression of methylene tetrahydrofolate dehydrogenase/cyclohydrolase. Across several data sets, expression of these target genes were associated with poorer outcomes in breast cancer patients. Importantly, a beneficial effect of miR-22 on clinical outcomes in breast cancer was shown to depend on the expression levels of the identified target genes, demonstrating the relevance of miRNA/mRNA interactions to disease progression in vivo. Our systematic analysis establishes miR-22 as a novel regulator of tumour cell metabolism, a function that could contribute to the role of this miRNA in cellular differentiation and cancer development. Moreover, we provide a paradigmatic example of effect modification in outcome analysis as a consequence of miRNA-directed gene targeting, a phenomenon that could be exploited to improve patient prognosis and treatment.

JOURNAL ARTICLE

Kyriakides M, Rama N, Sidhu J, Gabra H, Keun HC, El-Bahrawy Met al., 2016, Metabonomic analysis of ovarian tumour cyst fluid by proton nuclear magnetic resonance spectroscopy, ONCOTARGET, Vol: 7, Pages: 7216-7226, ISSN: 1949-2553

JOURNAL ARTICLE

Nevedomskaya E, Perryman R, Solanki S, Syed N, Mayboroda OA, Keun HCet al., 2016, A Systems Oncology Approach Identifies NT5E as a Key Metabolic Regulator in Tumor Cells and Modulator of Platinum Sensitivity, JOURNAL OF PROTEOME RESEARCH, Vol: 15, Pages: 280-290, ISSN: 1535-3893

JOURNAL ARTICLE

Perng W, Oken E, Roumeliotaki T, Sood D, Siskos AP, Chalkiadaki G, Dermitzaki E, Vafeiadi M, Kyrtopoulos S, Kogevinas M, Keun HC, Chatzi Let al., 2016, Leptin, acylcarnitine metabolites and development of adiposity in the Rhea mother-child cohort in Crete, Greece, OBESITY SCIENCE & PRACTICE, Vol: 2, Pages: 471-476, ISSN: 2055-2238

JOURNAL ARTICLE

Perryman R, O'Neill K, Keun H, Syed Net al., 2016, DETERMINING THE ROLE OF NICOTINAMIDE METABOLISM IN CHEMOSENSITIVITY IN GLIOBLASTOMA MULTIFORME, 21st Annual Scientific Meeting and Education Day of the Society-for-Neuro-Oncology, Publisher: OXFORD UNIV PRESS INC, Pages: 36-36, ISSN: 1522-8517

CONFERENCE PAPER

Valbuena GN, Rizzardini M, Cimini S, Siskos AP, Bendotti C, Cantoni L, Keun HCet al., 2016, Metabolomic Analysis Reveals Increased Aerobic Glycolysis and Amino Acid Deficit in a Cellular Model of Amyotrophic Lateral Sclerosis, MOLECULAR NEUROBIOLOGY, Vol: 53, Pages: 2222-2240, ISSN: 0893-7648

JOURNAL ARTICLE

Yogev O, Barker K, Sikka A, Almeida GS, Hallsworth A, Smith LM, Jamin Y, Ruddle R, Koers A, Webber HT, Raynaud FI, Popov S, Jones C, Petrie K, Robinson SP, Keun HC, Chesler Let al., 2016, p53 Loss in MYC-Driven Neuroblastoma Leads to Metabolic Adaptations Supporting Radioresistance, CANCER RESEARCH, Vol: 76, Pages: 3025-3035, ISSN: 0008-5472

JOURNAL ARTICLE

Athersuch TJ, Keun HC, 2015, Metabolic profiling in human exposome studies, MUTAGENESIS, Vol: 30, Pages: 755-762, ISSN: 0267-8357

JOURNAL ARTICLE

Fletcher ME, Boshier PR, Wakabayashi K, Keun HC, Smolenski RT, Kirkham PA, Adcock IM, Barton PJ, Takata M, Marczin Net al., 2015, Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 308, Pages: L1274-L1285, ISSN: 1040-0605

JOURNAL ARTICLE

Giskeodegard GF, Davies SK, Revell VL, Keun H, Skene DJet al., 2015, Diurnal rhythms in the human urine metabolome during sleep and total sleep deprivation, SCIENTIFIC REPORTS, Vol: 5, ISSN: 2045-2322

JOURNAL ARTICLE

Hendrickx DM, Aerts HJWL, Caiment F, Clark D, Ebbels TMD, Evelo CT, Gmuender H, Hebels DGAJ, Herwig R, Hescheler J, Jennen DGJ, Jetten MJA, Kanterakis S, Keun HC, Matser V, Overington JP, Pilicheva E, Sarkans U, Segura-Lepe MP, Sotiriadou I, Wittenberger T, Wittwehr C, Zanzi A, Kleinjans JCSet al., 2015, diXa: a data infrastructure for chemical safety assessment, BIOINFORMATICS, Vol: 31, Pages: 1505-1507, ISSN: 1367-4803

JOURNAL ARTICLE

Miller JA, Pappan K, Thompson PA, Want EJ, Siskos AP, Keun HC, Wulff J, Hu C, Lang JE, Chow H-HSet al., 2015, Plasma Metabolomic Profiles of Breast Cancer Patients after Short-term Limonene Intervention, CANCER PREVENTION RESEARCH, Vol: 8, ISSN: 1940-6207

JOURNAL ARTICLE

Parzych K, Chinn TM, Chen Z, Loaiza S, Porsch F, Valbuena GN, Kleijnen MF, Karadimitris A, Gentleman E, Keun HC, Auner HWet al., 2015, Inadequate fine-tuning of protein synthesis and failure of amino acid homeostasis following inhibition of the ATPase VCP/p97, CELL DEATH & DISEASE, Vol: 6, ISSN: 2041-4889

JOURNAL ARTICLE

Pomyen Y, Segura M, Ebbels TMD, Keun HCet al., 2015, Over-representation of correlation analysis (ORCA): a method for identifying associations between variable sets, BIOINFORMATICS, Vol: 31, Pages: 102-108, ISSN: 1367-4803

JOURNAL ARTICLE

Tredwell GD, Keun HC, 2015, convISA: A simple, convoluted method for isotopomer spectral analysis of fatty acids and cholesterol, METABOLIC ENGINEERING, Vol: 32, Pages: 125-132, ISSN: 1096-7176

JOURNAL ARTICLE

Chadeau-Hyam M, Vermeulen RCH, Hebels DGAJ, Castagne R, Campanella G, Portengen L, Kelly RS, Bergdahl IA, Melin B, Hallmans G, Palli D, Krogh V, Tumino R, Sacerdote C, Panico S, de Kok TMCM, Smith MT, Kleinjans JCS, Vineis P, Kyrtopoulos SAet al., 2014, Prediagnostic transcriptomic markers of Chronic lymphocytic leukemia reveal perturbations 10 years before diagnosis, ANNALS OF ONCOLOGY, Vol: 25, Pages: 1065-1072, ISSN: 0923-7534

JOURNAL ARTICLE

Chan PH, Zhang WL, Lau C-H, Cheung CY, Keun HC, Tsim KWK, Lam Het al., 2014, Metabonomic Analysis of Water Extracts from Different Angelica Roots by H-1-Nuclear Magnetic Resonance Spectroscopy, MOLECULES, Vol: 19, Pages: 3460-3470, ISSN: 1420-3049

JOURNAL ARTICLE

Keun H, 2014, Metabolomic Studies of Patient Material by High-Resolution Magic Angle Spinning Nuclear Magnetic Resonance Spectroscopy, CELL-WIDE METABOLIC ALTERATIONS ASSOCIATED WITH MALIGNANCY, Vol: 543, Pages: 297-313, ISSN: 0076-6879

JOURNAL ARTICLE

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