Sarcosine

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Improving the prediction of pathologic outcomes in patients undergoing radical prostatectomy: the value of prostate cancer antigen 3 (PCA3), prostate health index (phi) and sarcosine.[Pubmed:25667489]

Anticancer Res. 2015 Feb;35(2):1017-23.

BACKGROUND/AIM: Several efforts have been made to find biomarkers that could help clinicians to preoperatively determine prostate cancer (PCa) pathological characteristics and choose the best therapeutic approach, avoiding over-treatment. On this effort, prostate cancer antigen 3 (PCA3), prostate health index (phi) and Sarcosine have been presented as promising tools. We evaluated the ability of these biomarkers to predict the pathologic PCa characteristics within a prospectively collected contemporary cohort of patients who underwent radical prostatectomy (RP) for clinically localized PCa at a single high-volume Institution. MATERIALS AND METHODS: The prognostic performance of PCA3, phi and Sarcosine were evaluated in 78 patients undergoing RP for biopsy-proven PCa. Receiver operating characteristic (ROC) curve analyses tested the accuracy (area under the curve (AUC)) in predicting PCa pathological characteristics. Decision curve analyses (DCA) were used to assess the clinical benefit of the three biomarkers. RESULTS: We found that PCA3, phi and Sarcosine levels were significantly higher in patients with tumor volume (TV)>/=0.5 ml, pathologic Gleason sum (GS)>/=7 and pT3 disease (all p-valuesSarcosine showed a comparable AUC (0.85 [0.76-0.94]) only for T3 stage prediction, whereas PCA3 score showed lower AUCs, ranging from 0.74 (for GS) to 0.86 (for TV). CONCLUSION: PCA3, phi and Sarcosine are predictors of PCa characteristics at final pathology. Successful clinical translation of these findings would reduce the frequency of surveillance biopsies and may enhance acceptance of active surveillance (AS).

Implications of differences in expression of sarcosine metabolism-related proteins according to the molecular subtype of breast cancer.[Pubmed:24884785]

J Transl Med. 2014 May 28;12:149.

BACKGROUND: The goal of this study was to investigate the expression of Sarcosine metabolism-related proteins, namely glycine N-methyltransferase (GNMT), Sarcosine dehydrogenase (SARDH), and l-pipecolic acid oxidase (PIPOX), in the different breast cancer subtypes and to assess the implications of differences in expression pattern according to subtype. METHODS: We analyzed the expression of GNMT, SARDH, and PIPOX in a tissue microarray of 721 breast cancer cases using immunohistochemistry (IHC). We classified breast cancer cases into subtype luminal A, luminal B, HER-2, and triple negative breast cancer (TNBC) according to the status for the estrogen receptor (ER), progesterone receptor (PR), HER-2, and Ki-67. Sarcosine metabolism phenotype was stratified according to IHC results for GNMT, SARDH, and PIPOX: GNMT(+), SARDH and PIPOX(-) was classified as high Sarcosine type; GNMT(-), SARDH or PIPOX(-) as low Sarcosine type; GNMT(+), SARDH or PIPOX(+) as intermediate Sarcosine type, and GNMT(-), SARDH and PIPOX(-) as null type. RESULTS: Expression of Sarcosine metabolism-related proteins differed significantly according to breast cancer subtype (GNMT, p=0.005; SARDH, p=0.012; tumoral PIPOX, p=0.008; stromal PIPOX, p<0.001). These proteins were the most frequently expressed in HER-2 type tumors and the least in TNBC. Sarcosine metabolism phenotype also varied according to breast cancer subtype, with high Sarcosine type the most common in HER-2, and null type the most common in TNBC (p=0.003). Univariate analysis revealed that GNMT expression (p=0.042), tumoral PIPOX negativity (p=0.039), and high Sarcosine type (p=0.021) were associated with shorter disease-free survival (DFS). Multivariate analysis also revealed GNMT expression was an independent factor for shorter DFS (hazard ratio: 2.408, 95% CI: 1.154-5.024, p=0.019). CONCLUSION: Expressions of Sarcosine metabolism-related proteins varied according to subtype of breast cancer, with HER-2 type tumors showing elevated expression of these proteins, and TNBC subtype showing decreased expression of these proteins. Expression of Sarcosine metabolism-related proteins was also associated with breast cancer prognosis.

Effect of sarcosine on endothelial function relevant to angiogenesis.[Pubmed:25313747]

J Cancer Res Ther. 2014 Jul-Sep;10(3):603-10.

AIM OF STUDY: Endothelial cells (ECs) respond to changes in metabolic status and switch over to angiogenic phenotype. There are several metabolites known to mediate this transition; however, the effect of Sarcosine that accumulates in invasive prostate cancer is not known. The objective of the study was to examine whether Sarcosine influences EC function and affects angiogenesis. MATERIALS AND METHODS: The effect of Sarcosine was studied using different model systems including chick chorioallantoic membrane (CAM), rat aortic rings in culture, and human umbilical vein ECs (HUVECs) in culture. The statistical significance of difference was analyzed by one-way analysis of variance (ANOVA) and Student's t-test using GraphPad 5 software. RESULTS: Increased vascularization in CAM, increased endothelial sprouting in rat aortic rings in culture, and increased expression of CD31 and E-selectin suggested a possible angiogenic effect of Sarcosine. Sarcosine modulated expression of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). In ECs in culture LY294002, an inhibitor of phosphatidylinositol-3-kinase (PI3K)/Akt pathway and rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) reversed the effect of Sarcosine. Further, Sarcosine induced upregulation and activation of Akt in HUVECs. CONCLUSION: These results suggest that Sarcosine modulates EC function relevant to angiogenesis through modulation of PI3K/Akt/mTOR pathway.

Sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia.[Pubmed:24797328]

Neuroscience. 2014 Jun 20;271:160-9.

Brain ischemic tolerance is an endogenous protective mechanism activated by a preconditioning stimulus that is closely related to N-methyl-d-aspartate receptor (NMDAR). Glycine transporter type 1 (GlyT-1) inhibitors potentiate NMDAR and suggest an alternative strategy for brain preconditioning. The aim of this work was to evaluate the effects of brain preconditioning induced by Sarcosine, a GlyT-1 inhibitor, against global cerebral ischemia and its relation to NMDAR. Sarcosine was administered over 7 days (300 or 500 mg/kg/day, ip) before the induction of a global cerebral ischemia model in Wistar rats (male, 8-week-old). It was observed that Sarcosine preconditioning reduced cell death in rat hippocampi submitted to cerebral ischemia. Hippocampal levels of glycine were decreased in Sarcosine-treated animals, which was associated with a reduction of [(3)H] glycine uptake and a decrease in glycine transporter expression (GlyT-1 and GlyT-2). The expression of glycine receptors and the NR1 and NR2A subunits of NMDAR were not affected by Sarcosine preconditioning. However, Sarcosine preconditioning reduced the expression of the NR2B subunits of NMDAR. In conclusion, these data demonstrate that Sarcosine preconditioning induces ischemic tolerance against global cerebral ischemia and this neuroprotective state is associated with changes in glycine transport and reduction of NR2B-containing NMDAR expression.

Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia.[Pubmed:15023571]

Biol Psychiatry. 2004 Mar 1;55(5):452-6.

BACKGROUND: Hypofunction of N-methyl-D-aspartate glutamate receptor had been implicated in the pathophysiology of schizophrenia. Treatment with D-serine or glycine, endogenous full agonists of the glycine site of N-methyl-D-aspartate receptor, or D-cycloserine, a partial agonist, improve the symptoms of schizophrenia. N-methylglycine (Sarcosine) is an endogenous antagonist of glycine transporter-1, which potentiates glycine's action on N-methyl-D-aspartate glycine site and can have beneficial effects on schizophrenia. METHODS: Thirty-eight schizophrenic patients were enrolled in a 6-week double-blind, placebo-controlled trial of Sarcosine (2 g/d), which was added to their stable antipsychotic regimens. Twenty of them received risperidone. Measures of clinical efficacy and side effects were determined every other week. RESULTS: Patient who received Sarcosine treatment revealed significant improvements in their positive, negative, cognitive, and general psychiatric symptoms. Similar therapeutic effects were observed when only risperidone-treated patients were analyzed. Sarcosine was well-tolerated, and no significant side effect was noted. CONCLUSIONS: Sarcosine treatment can benefit schizophrenic patients treated by antipsychotics including risperidone. The significant improvement with the Sarcosine further supports the hypothesis of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Glycine transporter-1 is a novel target for the pharmacotherapy to enhance N-methyl-D-aspartate function.

Sarcosine is a glycine transporter type 1 (GlyT) inhibitor and an N-methyl-D-aspartate (NMDA) receptor co-agonist at the glycine binding site.

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