Identifying and targeting cancer-specific metabolism with network-based drug target prediction

Pacheco, Maria Pires; Bintener, Tamara Jean Rita; Ternes, Dominik; Kulms, Dagmar; Haan, Serge; Letellier, Elisabeth; Sauter, Thomas

doi:10.1016/j.ebiom.2019.04.046

Cited by 58 publications

(93 citation statements)

References 64 publications

(87 reference statements)

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“…Within this model GSH is involved in 124 reactions in cytosol, 22 in mitochondria, 15 in peroxisomes and 16 in the endoplasmic reticulum, showing its major involvement in a variety of cellular processes. Tissue- or phenotype-specific genome scale models can be derived from the general model with recent examples of cancer genome scale models provided by Pacheco et al, [ 175 ]. These authors developed methods for high throughput reconstruction of tissue specific models from genomics data and created over 10000 reconstructions of genome scale models for cancer tissues from RNA-Seq data included in the TCGA (The Cancer Genome Atlas) data set for 13 different types of cancers.…”

Section: Computer Modeling Of Gsh Metabolismmentioning

confidence: 99%

Role of Glutathione in Cancer: From Mechanisms to Therapies

et al. 2020

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Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects.

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Section: Computer Modeling Of Gsh Metabolismmentioning

confidence: 99%

Role of Glutathione in Cancer: From Mechanisms to Therapies

et al. 2020

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“…Metabolic models are powerful tools to identify metabolic alterations and mechanisms in human diseases such as Alzheimer’s [ 32 , 33 ], to predict biomarkers for inborn errors of metabolism [ 34 , 35 ], liver metabolism [ 36 , 37 ], pathogen infection of alveolar macrophages [ 38 ], obesity [ 39 ], Leigh syndrome fibroblasts [ 40 ], diabetes [ 41 ], co-morbidity [ 42 ], obesity and diabetes application have been reviewed in [ 43 ] as well as drug target prediction in cancer [ 12 , 14 , 18 , 44–52 ].…”

Section: Cancer and Metabolic Modellingmentioning

confidence: 99%

“…More interesting applications of genome-scale metabolic models are in silico knockout studies to discover cancer-specific essential genes [ 12 ] that could serve as potential drug targets or to identify oncometabolites by blocking the flux of the enzyme that consumes these metabolites [ 13 ]. A workflow using these approaches has previously been published [ 14 ] and is depicted in Figure 1 . Because the in vitro identification of drug targets and drug screenings is a meticulous task, with drug combination screenings having endless possibilities, metabolic modelling can be used to narrow down the number of targets, therefore reducing the time and costs of experiments.…”

Section: Introductionmentioning

confidence: 99%

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Towards the routine use of in silico screenings for drug discovery using metabolic modelling

Bintener

Pacheco²,

Sauter³

2020

Biochemical Society Transactions

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Currently, the development of new effective drugs for cancer therapy is not only hindered by development costs, drug efficacy, and drug safety but also by the rapid occurrence of drug resistance in cancer. Hence, new tools are needed to study the underlying mechanisms in cancer. Here, we discuss the current use of metabolic modelling approaches to identify cancer-specific metabolism and find possible new drug targets and drugs for repurposing. Furthermore, we list valuable resources that are needed for the reconstruction of cancer-specific models by integrating various available datasets with genome-scale metabolic reconstructions using model-building algorithms. We also discuss how new drug targets can be determined by using gene essentiality analysis, an in silico method to predict essential genes in a given condition such as cancer and how synthetic lethality studies could greatly benefit cancer patients by suggesting drug combinations with reduced side effects.

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“…En el área de la medicina, MFA y FBA se han utilizado ampliamente en la identificación de biomarcadores y la caracterización metabólica de células de cáncer (81)(82)(83) , evaluación de la interacción metabólica entre la microbiota intestinal con el desarrollo de alteraciones del intestino (84) , incluido cáncer (85) y en la identificación de blancos terapéuticos en bacterias patógenas como Mycobacterium tuberculosis (16,37,(86)(87)(88)(89) .…”

Section: Aplicaciones De Mfa/fbaunclassified

Conceptos básicos de análisis de fluxes metabólicos

Henao

Ramírez-Malule

López-Agudelo

2020

inycomp

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El metabolismo representa el nivel biológico que más se relaciona con los fenotipos de la célula y, las alteraciones o reprogramaciones de éste pueden, entre otras, (i) afectar la producción de metabolitos primarios o secundarios en microorganismos de interés biotecnológico, (ii) favorecer o no la inhibición del crecimiento en organismos patógenos y (iii) desarrollar desórdenes metabólicos como la obesidad o la diabetes. Es por ello, que el estudio del metabolismo, el rediseño, y el redireccionamiento de fluxes metabólicos se ha convertido en un área importante de investigación (también conocida como Ingeniería Metabólica), ya que ha permitido el desarrollo y diseño de procesos biológicos mejorados, la identificación de blancos terapéuticos, el diseño de estrategias terapéuticas para curar desordenes metabólicos y la identificación de biomarcadores en cáncer, entre otros. Actualmente, se han desarrollado metodologías computacionales que permiten estudiar el metabolismo celular a diferentes condiciones medioambientales, dirigiendo la experimentación con las predicciones del modelo. El propósito de esta revisión es resaltar la importancia del análisis de fluxes metabólicos como una metodología general para estudiar la reprogramación metabólica en distintos organismos de interés biotecnológico, médico, y terapéutico. Este trabajo condensa las bases teóricas y los conceptos claves para entender el análisis de fluxes metabólicos, lo cual será un insumo fundamental para aquellos que se están adentrando al mundo de la biología de sistemas o áreas afines.

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Identifying and targeting cancer-specific metabolism with network-based drug target prediction

Cited by 58 publications

References 64 publications

Role of Glutathione in Cancer: From Mechanisms to Therapies

Role of Glutathione in Cancer: From Mechanisms to Therapies

Towards the routine use of in silico screenings for drug discovery using metabolic modelling

Conceptos básicos de análisis de fluxes metabólicos

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