The inhibition of accumulation of [1-14C]glycine and its incorporation into protein of Ehrlich ascites-carcinoma cells by DL-methionine.
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ABSTRACT:
SUBMITTER: Kovacevic Z
PROVIDER: S-EPMC1270438 | biostudies-other | 1967 May
REPOSITORIES: biostudies-other
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Project description:The specific radioactivity of urinary hippurate glycine was determined after injecting guinea pigs with benzoate and either dl-[2-(14)C]glutamate or dl-[5-(14)C]glutamate. The isotope dilution factor for the formation of [(14)C]glycine was significantly greater (30%) with C-2 labelled glutamate. With either form of labelled glutamate the hippurate glycine was largely carboxyl-group labelled. The observations suggest a route for the incorporation of glutamate carbon into glycine that involves C-5 but not C-2. A hypothesis for glycine biosynthesis from l-glutamate is advanced, consistent with these findings, that includes conversion of l-glutamate to 4-hydroxy-2-oxoglutarate, the scission of the latter to glyoxylate and pyruvate, and the formation of glycine by transamination.
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Project description:Cancer cells exhibit an increased glycolysis rate for ATP generation (the Warburg effect) to sustain an increased proliferation rate. In tumor cells, the oxidation of pyruvate in the Krebs cycle is substituted by lactate production, catalyzed by LDH. In this study, we use ethoxyquin (EQ) as a novel inhibitor to target LDH in murine Ehrlich ascites carcinoma (EAC) and as a combination therapy to improve the therapeutic efficacy of the conventional chemotherapy drug, cisplatin (CIS). We investigated the anti-tumor effect of EQ on EAC-bearing mice and checked whether EQ can sustain the anti-tumor potential of CIS and whether it influences LDH activity. Treatment with EQ had evident anti-tumor effects on EAC as revealed by the remarkable decrease in the expression of the anti-apoptotic gene Bcl-2 and by a significant increase in the expression of apoptotic genes (BAX and caspase-3). EQ also caused a significant decrease in the autophagic activity of EAC cells, as shown by a reduction in the fluorescence intensity of the autophagosome marker. Additionally, EQ restored the altered hematological and biochemical parameters and improved the disrupted hepatic tissues of EAC-bearing mice. Co-administration of EQ and CIS showed the highest anti-tumor effect against EAC. Collectively, our findings propose EQ as a novel inhibitor of LDH in cancer cells and as a combinatory drug to increase the efficacy of cisplatin. Further studies are required to validate this therapeutic strategy in different cancer models and preclinical trials.
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Project description:Cardiomyopathy is one of the characteristic features of cancer. In this study, we establish a suitable model to study breast cancer-induced cardiomyopathy in mice. We used Ehrlich Ascites Carcinoma cells to induce subcutaneous tumor in 129/SvJ mice and studied its effect on heart function. In Ehrlich Ascites Carcinoma bearing mice, we found significant reduction in left ventricle wall thickness, ejection fraction, and fractional shortening increase in left ventricle internal diameter. We found higher muscle atrophy, degeneration, fibrosis, expression of cell-adhesion molecules and cell death in tumor-bearing mice hearts. As observed in cancer patients, we found that mTOR, a key signalling molecule responsible for maintaining cell growth and autophagy was suppressed in this model. Tumor bearing mice hearts show increased expression and nuclear localization of TFEB and FoxO3a transcription factors, which are involved in the upregulation of muscle atrophy genes, lysosomal biogenesis genes and autophagy genes. We propose that Ehrlich Ascites Carcinoma induced tumor can be used as a model to identify potential therapeutic targets for the treatment of heart failure in patients suffering from cancer-induced cardiomyopathy. This model can also be used to test the adverse consequences of cancer chemotherapy in heart.
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Project description:1. Lactating mammary glands of sheep were perfused for several hours in the presence of dl-[2-(14)C]ornithine or dl-[5-(14)C]arginine and received adequate quantities of acetate, glucose and amino acids. 2. In the [(14)C]ornithine experiment 1.4% of the casein and 1% of the expired carbon dioxide came from added ornithine; 96% of the total radioactivity in casein was recovered in proline; 13% of the proline of casein originated from plasma ornithine. 3. In this experiment the results of chemical degradation of proline of casein as well as relative specific activities in the isolated products are consistent with the view that ornithine is metabolized, by way of glutamic gamma-semialdehyde, to proline or glutamic acid. 4. In the [(14)C]arginine experiments 3% of the casein and 1% of the expired carbon dioxide came from arginine; 84% of the arginine and 9% of the proline of casein originated from plasma arginine. 5. In these experiments the relative specific activities of arginine, ornithine and proline in plasma are in agreement with the view that arginine is metabolized by way of ornithine to proline. The conversion of arginine into ornithine is probably catalysed by arginase, so that arginase in mammary tissue may be involved in the process of milk synthesis.
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Project description:The aim of this study is to investigate the antitumor activity and possible molecular mechanism of Phenethyl isothiocyanate (PEITC) against Ehrlich ascites carcinoma in-vivo and in-vitro. In-vivo, ascetic fluid volume, body weight, serum malondialdehyde (MDA) level and total antioxidant capacity (TAC) were determined using Ehrlich ascites carcinoma (EAC) bearing mice. In-vitro, MTT assay was used. RT-PCR was used to investigate role of PEITC in apoptosis by analyzing the expression of Bax, caspase-9, and Bcl-2 genes. The effect of PEITC on caspase-9 enzyme activity was also tested. PEITC and/or Doxorubicin (Dox) treatment significantly suppressed EAC growth as compared to EAC/oil control mice. PEITC treatment showed a dose-dependent inhibition of EAC cells as indicated by MTT assay. We found that significant increase in MDA level and decrease in TAC caused by Dox treatment were significantly reduced by combination with PEITC treatment. Bax, caspase-9 genes' expression and caspase-9 enzymatic activity were significantly increased, while Bcl-2 gene expression was significantly decreased in PEITC treated mice. PEITC may act as a promising anticancer agent either alone or more effectively in combination with Dox through apoptotic cell death induction.
| S-EPMC6269550 | biostudies-literature
Project description:Cancer is the second leading cause of mortality accounting for one in every six deaths globally. Plant secondary metabolites, among them polyphenols, represent an effective and much safer alternative approach to the currently available medications. In this work, utilizing LC-MS/MS, we characterized the constituents of S. yapa leaves extract and evaluated its antioxidant and anticancer properties. In total, 34 secondary metabolites, mainly flavonoids (Tricin, luteolin, and apigenin and their glucosides as well as sulfated derivatives) were identified. The extract manifested substantial antioxidant activity in DPPH assay, and high total phenolic content determined by Folin Ciocalteu method. The extract was safe up to 4800 mg/kg b.wt. when administered orally in mice and neither affected the hematological parameters nor the liver enzyme levels at the studied dose (LD50, 480 mg, kg b.wt.). In the treated animals, the extract surpassed the reference drug (5-flouro uracil) and significantly reduced the tumor volume and weight by 71.50 and 85.46%, respectively, increased the median survival time to 53.2 days and the lifespan by 116%. The extract improved all the hematological parameters, where it increased the hemoglobin (Hb) concentration, red blood cell (RBC) count, packed cell volume (PVC) and platelets by 58.21, 8.98, 9.89 and 120%, respectively, compared to the untreated EAC bearing animals. Additionally, the extract significantly declined the elevated levels of ALT and AST enzymes by 29.18% and 59.88%, respectively. In molecular docking, the annotated flavonoids displayed appreciable binding affinities to the active sites of VEGFR1 and VEGFR2. In conclusion, Saba yapa is a promising plant that can be introduced to further advanced clinical studies for the development of novel anticancer drugs with lower side effects.
| S-EPMC8117008 | biostudies-literature
Project description:1. Ehrlich ascites-cell extracts convert choline and ethanolamine approximately equally well into their respective phosphoryl derivatives. 2. Choline is a potent inhibitor of ethanolamine phosphorylation, but ethanolamine has little effect on choline phosphorylation. 3. 2,3-Dimercaptopropanol, cysteine and Ca(2+) inhibit ethanolamine phosphorylation, but have no detectable effect on choline phosphorylation. 4. Choline-phosphorylating activity in Ehrlich ascites-cell extracts is more stable during storage than ethanolamine-phosphorylating activity. 5. Choline phosphorylation is stimulated in the presence of benzoylcholine, succinylcholine, butyrylcholine and propionylcholine, whereas ethanolamine phosphorylation is inhibited. This relationship is reciprocal: the compounds causing the greatest stimulation of choline phosphorylation bring about the greatest inhibition of ethanolamine phosphorylation.
| S-EPMC1198337 | biostudies-other
Project description:1. Aerobic or anaerobic incubation at 37 degrees of Ehrlich ascites-carcinoma cells in Krebs-Ringer bicarbonate medium containing glucose and labelled thiamine results in accumulation in the cell of labelled thiamine, so that the concentration of total labelled thiamine in the cells greatly exceeds (by a factor 7) that in the medium. This concentration ratio is approximately constant for small initial external concentrations of labelled thiamine but diminishes when the latter exceed 0.4mum. 2. All the labelled thiamine in the tumour cells is present as thiamine phosphates. 3. The uptake of labelled thiamine is markedly diminished by decrease of temperature. At 9 degrees concentration ratio (cells/medium) 0.5 is observed whereas at 37 degrees the concentration ratio is 8.6. 4. The extent of phosphorylation of labelled thiamine depends on the period of incubation. 5. The influx of labelled thiamine is diminished by the presence of its analogues, pyrithiamine and Amprol, and also by the presence of thiamine monophosphate and thiamine diphosphate, which are potent inhibitors of thiamine phosphorylation in Ehrlich ascites cells. 6. Labelled thiamine phosphates leak from the cell into the medium, so that eventually all the labelled thiamine, both in the cell and medium, is converted into thiamine phosphates. However, in the presence of 2,4-dinitrophenol (0.1mm) and iodoacetate (1mm) thiamine phosphorylation is diminished, the concentration ratio for labelled thiamine (cells/medium) falls to half its normal value and little or no labelled thiamine phosphates leaks into the medium. 7. In the presence of thiamine phosphates, free labelled thiamine accumulates in Ehrlich ascites cells against a concentration gradient, concentration ratios (cells/medium) greater than unity being evident. 8. The evidence supports the conclusion that thiamine is transferred into the Ehrlich ascites cell by a carrier-mediated energy-assisted process.
| S-EPMC1265068 | biostudies-other
Project description:(-)-Emetine has little or no effect on O(2) consumption of Ehrlich ascites-cell suspensions or on the viability of transplanted Ehrlich ascites-tumour cells exposed to, or incubated with, the drug in vitro before inoculation into new-host mice. (-)-Emetine administered as a single injection to mice bearing Ehrlich ascites-tumour cells slows the growth rate of the tumour. The subcutaneous or intraperitoneal injection of the drug depresses protein and DNA synthesis of the tumour cells in vivo in a reversible manner. Mice bearing ascitic sarcoma 180 or Ehrlich ascites-tumour cells when given a course of treatment with (-)-emetine or (-)-O-methyltubulosine have a substantially lower tumour load than untreated controls and correspondingly longer survival times.
| S-EPMC1167974 | biostudies-other
Project description:The effect of methylglyoxal on the oxygen consumption of Ehrlich-ascites-carcinoma (EAC)-cell mitochondria was tested by using different respiratory substrates, electron donors at different segments of the mitochondrial respiratory chain and site-specific inhibitors to identify the specific respiratory complex which might be involved in the inhibitory effect of methylglyoxal on the oxygen consumption by these cells. The results indicate that methylglyoxal strongly inhibits ADP-stimulated alpha-oxo-glutarate and malate plus pyruvate-dependent respiration, whereas, at a much higher concentration, methylglyoxal fails to inhibit succinate-dependent respiration. Methylglyoxal also fails to inhibit respiration which is initiated by duroquinol, an artificial electron donor. Moreover, methylglyoxal cannot inhibit oxygen consumption when the NNN'N'-tetramethyl-p-phenylenediamine by-pass is used. The inhibitory effect of methylglyoxal is identical on both ADP-stimulated and uncoupler-stimulated respiration. Lactaldehyde, a catabolite of methylglyoxal, can exert a protective effect on the inhibition of EAC-cell mitochondrial respiration by methylglyoxal. We suggest that methylglyoxal possibly inhibits the electron flow through complex I of the EAC-cell mitochondrial respiratory chain.
| S-EPMC1137558 | biostudies-other