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Use of nuclear magnetic resonance-based metabolomics in detecting drug resistance in cancer.

ABSTRACT: Cancer cells possess a highly unique metabolic phenotype, which is characterized by high glucose uptake, increased glycolytic activity, decreased mitochondrial activity, low bioenergetic and increased phospholipid turnover. These metabolic hallmarks can be readily assessed by metabolic technologies - either in vitro or in vivo - to monitor responsiveness and resistance to novel targeted drugs, where specific inhibition of cell proliferation (cytostatic effect) occurs rather than direct induction of cell death (cytotoxicity). Using modern analytical technologies in combination with statistical approaches, 'metabolomics', a global metabolic profile on patient samples can be established and validated for responders and nonresponders, providing additional metabolic end points. Discovered metabolic end points should be translated into noninvasive metabolic imaging protocols.

SUBMITTER: Merz AL

PROVIDER: S-EPMC2756767 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Use of nuclear magnetic resonance-based metabolomics in detecting drug resistance in cancer.

Merz Andrea L AL Serkova Natalie J NJ

Biomarkers in medicine 20090601 3

Cancer cells possess a highly unique metabolic phenotype, which is characterized by high glucose uptake, increased glycolytic activity, decreased mitochondrial activity, low bioenergetic and increased phospholipid turnover. These metabolic hallmarks can be readily assessed by metabolic technologies - either in vitro or in vivo - to monitor responsiveness and resistance to novel targeted drugs, where specific inhibition of cell proliferation (cytostatic effect) occurs rather than direct induction ...[more]

PMID: 20160999

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Project description:Naphthalene, the most common polycyclic aromatic hydrocarbon, causes airway epithelium injury in mice. Repeated exposure of mice to naphthalene induces airway epithelia that are resistant to further injury. Previous studies revealed that alterations in bioactivation enzymes and increased levels of gamma-glutamylcysteine synthase in the bronchioles protect tolerant mice from naphthalene and its reactive metabolites. In our current study, tolerance was induced in male ICR mice using a total of 7 daily intraperitoneal injections of naphthalene (200 mg/kg). Both naphthalene-tolerant and non-tolerant mice were challenged with a dose of 300 mg/kg naphthalene on day 8 to investigate metabolite differences. The lungs, liver, and kidneys were collected for histopathology 24 h after the challenge dose. Bronchial alveolar lavage fluid (BALF) and both hydrophilic and hydrophobic extracts from each organ were analyzed using nuclear magnetic resonance (NMR)-based metabolomics. The histological results showed no observable injuries to the airway epithelium of naphthalene-tolerant mice when compared with the control. In contrast, airway injuries were observed in mice given a single challenge dose (injury mice). The metabolomics analysis revealed that the energy metabolism in the lungs of tolerant and injury mice was significantly perturbed. However, antioxidant metabolites, such as glutathione and succinate, were significantly increased in the lungs of tolerant mice, suggesting a role for these compounds in the protection of organs from naphthalene-induced electrophilic metabolites and free radicals. Damage to the airway cellular membrane, as shown by histopathological results and increased acetone in the BALF and perturbation of hydrophobic lung extracts, including cholesterol, phosphorylcholine-containing lipids, and fatty acyl chains, were observed in injury mice. Consistent with our histopathological results, fewer metabolic effects were observed in the liver and kidney of mice after naphthalene treatments. In conclusion, NMR-based metabolomics reveals possible mechanisms of naphthalene tolerance and naphthalene-induced toxicity in the respiratory system of mice.

Project description:UnlabelledDengue, due to its global burden, is the most important arthropod-borne flavivirus disease, and early detection lowers fatality rates to below 1%. Since the metabolic resources crucial for viral replication are provided by host cells, detection of changes in the metabolic profile associated with disease pathogenesis could help with the identification of markers of prognostic and diagnostic importance. We applied (1)H nuclear magnetic resonance exploratory metabolomics to study longitudinal changes in plasma metabolites in a cohort in Recife, Brazil. To gain statistical power, we used innovative paired multivariate analyses to discriminate individuals with primary and secondary infection presenting as dengue fever (DF; mild) and dengue hemorrhagic fever (DHF; severe) and subjects with a nonspecific nondengue (ND) illness (ND subjects). Our results showed that a decrease in plasma low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) discriminated dengue virus (DENV)-infected subjects from ND subjects, and also, subjects with severe infection even presented a decrease in lipoprotein concentrations compared to the concentrations in subjects with mild infection. These results add to the ongoing discussion that the manipulation of lipid metabolism is crucial for DENV replication and infection. In addition, a decrease in plasma glutamine content was characteristic of DENV infection and disease severity, and an increase in plasma acetate levels discriminated subjects with DF and DHF from ND subjects. Several other metabolites shown to be altered in DENV infection and the implications of these alterations are discussed. We hypothesize that these changes in the plasma metabolome are suggestive of liver dysfunction, could provide insights into the underlying molecular mechanisms of dengue virus pathogenesis, and could help to discriminate individuals at risk of the development of severe infection and predict disease outcome.ImportanceDengue, due to its global burden, is the most important mosquito-borne viral disease. There is no specific treatment for dengue disease, and early detection lowers fatality rates to below 1%. In this study, we observed the effects of dengue virus infection on the profile of small molecules in the blood of patients with mild and severe infection. Variations in the profiles of these small molecules reflected the replication of dengue virus in different tissues and the extent of tissue damage during infection. The results of this study showed that the molecules that changed the most were VLDL, LDL, and amino acids. We propose that these changes reflect liver dysfunction and also that they can be used to discriminate subjects with mild dengue from those with severe dengue.

Dataset Information

Use of nuclear magnetic resonance-based metabolomics in detecting drug resistance in cancer.

Publications

Use of nuclear magnetic resonance-based metabolomics in detecting drug resistance in cancer.

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