Plasma Metabolomics for Discovery of Early Metabolic Markers of Prostate Cancer Based on Ultra-High-Performance Liquid Chromatography-High Resolution Mass Spectrometry.

Background: The prevention and early screening of PCa is highly dependent on the identification of new biomarkers. In this study, we investigated whether plasma metabolic profiles from healthy males provide novel early biomarkers associated with future risk of PCa.

Methods: Using the (SU.

NMR metabolomic profiles associated with long-term risk of prostate cancer.

Introduction: Prostate cancer is a multifactorial disease whose aetiology is still not fully understood. Metabolomics, by measuring several hundred metabolites simultaneously, could enhance knowledge on the metabolic changes involved and the potential impact of external factors.

Objectives: The aim of the present study was to investigate whether pre-diagnostic plasma metabolomic profiles were associated with the risk of developing a prostate cancer within the following decade.

Two Metabolomics Phenotypes of Human Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease According to Fibrosis Severity.

Non-Alcoholic Fatty Liver Disease (NAFLD) is considered as the forthcoming predominant cause for hepatocellular carcinoma (HCC). NAFLD-HCC may rise in non-cirrhotic livers in 40 to 50% of patients. The aim of this study was to identify different metabolic pathways of HCC according to fibrosis level (F0F1 vs.

Untargeted plasma metabolomic profiles associated with overall diet in women from the SU.VI.MAX cohort.

Purpose: Dietary intakes are reflected in plasma by the presence of hundreds of exogenous metabolites and variations in endogenous metabolites. The exploration of diet-related plasma metabolic profiles could help to better understand the impact of overall diet on health. Our aim was to identify metabolomic signatures reflecting overall diet in women from the French general population.

Plasma Metabolomic Signatures Associated with Long-term Breast Cancer Risk in the SU.VI.MAX Prospective Cohort.

Background: Breast cancer is a major cause of death in occidental women. The role of metabolism in breast cancer etiology remains unclear. Metabolomics may help to elucidate novel biological pathways and identify new biomarkers to predict breast cancer long before symptoms appear.

NMR metabolomics of fibroblasts with inherited mitochondrial Complex I mutation reveals treatment-reversible lipid and amino acid metabolism alterations.

Introduction: Elucidating molecular alterations due to mitochondrial Complex I (CI) mutations may help to understand CI deficiency (CID), not only in mitochondriopathies but also as it is caused by drugs or associated to many diseases.

Objectives: CID metabolic expression was investigated in Leber's hereditary optic neuropathy (LHON) caused by an inherited mutation of CI.

Methods: NMR-based metabolomics analysis was performed in intact skin fibroblasts from LHON patients.

NMR metabolomic signatures reveal predictive plasma metabolites associated with long-term risk of developing breast cancer.

Background: Combination of metabolomics and epidemiological approaches opens new perspectives for ground-breaking discoveries. The aim of the present study was to investigate for the first time whether plasma untargeted metabolomic profiles, established from a simple blood draw from healthy women, could contribute to predict the risk of developing breast cancer within the following decade and to better understand the aetiology of this complex disease.

Methods: A prospective nested case-control study was set up in the Supplémentation en Vitamines et Minéraux Antioxydants (SU.

Specificities of Human Hepatocellular Carcinoma Developed on Non-Alcoholic Fatty Liver Disease in Absence of Cirrhosis Revealed by Tissue Extracts ¹H-NMR Spectroscopy.

There is a rising incidence of non-alcoholic fatty liver disease (NAFLD) as well as of the frequency of Hepato-Cellular Carcinoma (HCC) associated with NAFLD To seek for putative metabolic pathways specific of the NAFLD etiology, we performed comparative metabolomics between HCC associated with NAFLD and HCC associated with cirrhosis. The study included 28 pairs of HCC tissue versus distant Non-Tumoral Tissue (NTT) collected from patients undergoing hepatectomy. HCC was associated with cirrhosis ( = 9), normal liver ( = 6) and NAFLD ( = 13).

Metabolomics and transcriptomics demonstrate severe oxidative stress in both localized chemotherapy-treated and bystander tumors.

Background: Localized radiotherapy is long known to cause damages to not only targeted but also non-targeted cells, the so-called bystander (BS) effect. Recently, BS effect was demonstrated in response to chemotherapy. To get further insight into the mechanism of chemotherapy-induced BS effect in vivo, we investigated the response of normal tissues and untreated BS melanomas, at distance from localized chemotherapy-treated melanomas.

Normal human melanocytes exposed to chronic insulin and glucose supplementation undergo oncogenic changes and methyl group metabolism cellular redistribution.

Recent epidemiological studies have suggested a link between cancer and pathophysiological conditions associated with hyperinsulinemia. In this report, we address the possible role of insulin exposure in melanocyte transformation. To this aim, normal melanocytes were exposed to chronic insulin and glucose supplementation (twice the standard medium concentration) for at least 3 wk.

Cell cycle-dependent conjugation of endogenous BRCA1 protein with SUMO-2/3.

Background: BRCA1, the main breast and ovarian cancer susceptibility gene, has a key role in maintenance of genome stability, cell cycle and transcription regulation. Interestingly, some of the numerous proteins which interact with BRCA1 protein undergo conjugation with small ubiquitin-like modifiers (SUMO). This post-translational modification is related to transcription, DNA repair, nuclear transport, signal transduction, and to cell cycle stress response.

Quantitative two-dimensional HRMAS 1H-NMR spectroscopy-based metabolite profiling of human cancer cell lines and response to chemotherapy.

NMR spectroscopy-based metabolomics still needs development in quantification procedures. A method was designed for quantitative two-dimensional high resolution magic angle spinning (HRMAS) proton-NMR spectroscopy-based metabolite profiling of intact cells. It uses referencing of metabolite-related NMR signals to protein-related NMR signals and yields straightforward and automatable metabolite profiling.

A model of phospholipid biosynthesis in tumor in response to an anticancer agent in vivo.

We study, in this paper, a model for the core of the system of the Glycerophospholipid metabolism in the murine cells. It comprises the simple and enzymatic reactions of PhosphatidylEthanolamine and the PhosphatidylCholine. The model's general structure is taken from a number of books and articles.

Combined methionine deprivation and chloroethylnitrosourea have time-dependent therapeutic synergy on melanoma tumors that NMR spectroscopy-based metabolomics explains by methionine and phospholipid metabolism reprogramming.

Methionine (Met) deprivation stress (MDS) is proposed in association with chemotherapy in the treatment of some cancers. A synergistic effect of this combination is generally acknowledged. However, little is known on the mechanism of the response to this therapeutic strategy.

Mitochondrial bioenergetic background confers a survival advantage to HepG2 cells in response to chemotherapy.

Cancer cells mainly rely on glycolysis for energetic needs, and mitochondrial ATP production is almost inactive. However, cancer cells require the integrity of mitochondrial functions for their survival, such as the maintenance of the internal membrane potential gradient (DeltaPsim). It thus may be predicted that DeltaPsim regeneration should depend on cellular capability to produce sufficient ATP by upregulating glycolysis or recruiting oxidative phosphorylation (OXPHOS).

Optimal methionine-free diet duration for nitrourea treatment: a Phase I clinical trial.

In animal models, methionine (MET) restriction in association with chloroethylnitrosoureas led to a substantial improvement. On this basis, we initiated a Phase I clinical trial of dietary MET restriction in association with chloroethylnitrosourea (cystemustine) treatment for patients with recurrent glioma or metastatic melanoma. Our purpose was 1) to determine the optimal MET-free diet duration for a maximum depletion of plasma MET and 2) to evaluate the feasibility of this association.

Chemotherapy-induced bystander effect in response to several chloroethylnitrosoureas: an origin independent of DNA damage?

Chloroethylnitrosourea (CENU) chemotherapy is used for the treatment of melanoma tumors. The main mechanism of action of this anticancer agent is via DNA damage. We recently showed in murine experiments using a parental double B16 melanoma tumor model that, after treatment of primary tumors with cystemustine (CENU agent), untreated secondary tumors exhibited growth inhibition and metabolism disorders.

PP2A activity is controlled by methylation and regulates oncoprotein expression in melanoma cells: a mechanism which participates in growth inhibition induced by chloroethylnitrosourea treatment.

Protein phosphatase 2A (PP2A), an Akt pathway inhibitor, is considered to be activated by methylation of its catalytic subunit. Also PP2A downregulation was proposed to take part in carcinogenesis. Recently, PP2A activation was shown to be activated in response to DNA damage.

A methionine-free diet associated with nitrosourea treatment down-regulates methylguanine-DNA methyl transferase activity in patients with metastatic cancer.

Background: Methionine (MET) depletion used in association with chemotherapy improves the therapeutic index in animal models. This potentiating effect may be due to tumor cell sensitization to chloroethylnitrosoureas through their MET dependency and the down-regulation of O6- methylguanine-DNA methyltransferase (MGMT). Our purpose was to evaluate the impact of the association of a dietary MET restriction with nitrosourea treatment on MGMT activity in peripheral blood mononuclear cells (PBMCs).

Metabolomics by proton nuclear magnetic resonance spectroscopy of the response to chloroethylnitrosourea reveals drug efficacy and tumor adaptive metabolic pathways.

Metabolomics of tumors may allow discovery of tumor biomarkers and metabolic therapeutic targets. Metabolomics by two-dimensional proton high-resolution magic angle spinning nuclear magnetic resonance spectroscopy was applied to investigate metabolite disorders following treatment by chloroethylnitrosourea of murine B16 melanoma (n = 33) and 3LL pulmonary carcinoma (n = 31) in vivo. Treated tumors of both types resumed growth after a delay.

Methionine-dependence phenotype of tumors: metabolite profiling in a melanoma model using L-[methyl-13C]methionine and high-resolution magic angle spinning 1H-13C nuclear magnetic resonance spectroscopy.

Tumors frequently have abnormal L-methionine (Met) metabolism, the so-called Met-dependence phenotype that refers to the inability to proliferate in the absence of Met. However, the origin of this phenotype is still unknown and may arise from one of several pathways of Met metabolism. To help characterize the metabolic features of Met-dependent/independent phenotypes, the fate of the methyl carbon of L-[methyl-13C]Met was chased in a murine model of malignant melanoma (B16-F1) in vitro and in vivo.

Bystander effects are induced by CENU treatment and associated with altered protein secretory activity of treated tumor cells: a relay for chemotherapy?

In a previous study, it was reported that secondary untreated melanoma tumors implanted several weeks after and at distance from primary chloroethylnitrosourea (CENU)-treated tumors underwent differentiation and growth inhibition. To see whether the primary treated tumor released soluble factors that mediated the secondary tumor response, serum transfer experiments were performed in vivo. Administration of serum from CENU-treated tumor-bearing donors arrested tumor proliferation, decreased vessel formation and induced tumor metabolite alterations encompassing glutathione decrease and polyunsaturated fatty acid and phosphoethanolamine increase.

Response of melanoma tumor phospholipid metabolism to chloroethyle nitrosourea: a high resolution proton NMR spectroscopy study.

Phospholipid metabolism is tightly involved in tumor growth regulation and tumor cell survival. The response of phospholipid metabolism to chloroethyle nitrosourea treatment is investigated in a murine B16 melanoma model. Measurements of phospholipid derivatives are performed on intact tumor tissue samples using one- and two-dimensional proton NMR spectroscopy.