Transfer of intestine-derived diamines into tumour cells during treatment of Ehrlich-ascites--carcinoma-bearing mice with polyamine anti-metabolites.
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ABSTRACT:
SUBMITTER: Kallio A
PROVIDER: S-EPMC1153385 | biostudies-other | 1984 Mar
REPOSITORIES: biostudies-other
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Project description:1. Ehrlich ascites-carcinoma cells contained relatively high concentrations of spermidine and spermine, but the putrescine content of the washed cells was less than 10% of that of higher polyamines. 2. Ascites-tumour cells likewise exhibited high activities of L-ornithine decarboxylase (EC 4.1.1.17), S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), spermidine synthase (EC 2.5.1.16) and spermine synthase. 3. During the first days after the inoculation, the polyamine pattern of the ascites cells was characterized by a high molar ratio of spermidine to spermine, which markedly decreased on aging of the cells. 4. Various diamines injected into mice bearing ascites cells rapidly and powerfully decreased ornithine decarboxylase activity in the carcinoma cells, apparently through a mechanism that was not a direct inhibition of the enzyme in vitro. Cadaverine (1,5-diaminopentane) and 1,6-diaminohexane were the most potent inhibitors of ornithine decarboxylase among the amines tested. 5. Chronic treatment of the mice with diamines resulted in a virtually complete disappearance of ornithine decarboxylase activity, and after 24h a significant decline in spermidine accumulation. 6. Cadaverine appeared to be an especially suitable compound for use as an inhibitor of the synthesis of higher polyamines, at least in Ehrlich ascites cells, since this diamine also acted as a competitive inhibitor for putrescine in the spermidine synthase reaction without being incorporated into the higher polyamines.
| S-EPMC1164960 | biostudies-other
Project description:The aim of this study was to investigate the therapeutic potential of resveratrol in combination with cisplatin on the inhibition of tumour angiogenesis, growth, and macrophage polarization in mice bearing the solid form of an Ehrlich ascites tumour (EAT) that were exposed to whole-body hyperthermia treatment. In addition, we investigated whether a multimodal approach with hyperthermia and resveratrol could abolish cisplatin resistance in tumour cells through the modulation of histone deacetylase (HDAC) activity and levels of heat shock proteins (HSP70/HSP90) and contribute to the direct toxicity of cisplatin on tumour cells. The tumour was induced by injecting 1 × 106 EAT cells subcutaneously (sc) into the thighs of Balb/c mice. The mice were treated with resveratrol per os for five consecutive days beginning on day 2 after tumour injection and/or by injecting cisplatin intraperitoneally (ip) at a dose of 2.5 mg/kg on days 10 and 12 and at a dose of 5 mg/kg on day 15. Immediately thereafter, the mice were exposed to systemic hyperthermia for 15 min at a temperature of 41 °C. The obtained results showed that the administration of resveratrol did not significantly contribute to the antitumour effect of cisplatin and hyperthermia, but it partially contributed to the immunomodulatory effect and to the reduction of cisplatin toxicity and to a slight increase in animal survival. This treatment schedule did not affect microvessel density, but it inhibited tumour growth and modulated macrophage polarization to the M1 phenotype. Furthermore, it abolished the resistance of tumour cells to cisplatin by modulating HDAC activity and the concentration of HSP70 and HSP90 chaperones, contributing to the increased lifespan of mice. However, the precise mechanism of the interaction between resveratrol, cisplatin, and hyperthermia needs to be investigated further.
| S-EPMC10341868 | biostudies-literature
Project description:To examine the effects of the presence of Ehrlich ascites tumours on both the catalytic unit and the substrate/product translocase components of the glucose-6-phosphatase system in vivo, we isolated microsomes from the livers of control and tumour-bearing mice. Samples were analysed immunochemically for the quantity of catalytic unit, stabilizing protein and translocases T2 and T3 proteins. In comparison experiments, a variety of kinetic studies were performed. The most striking findings in tumour-bearing mice were: a 2.5-fold increase in the quantity of translocase T2 protein; increases in the Km and Vmax. for glucose 6-phosphate phosphohydrolase; and a decrease in the Km value for carbamoyl phosphate (carbamoyl-P) of carbamoyl-P:glucose phosphotransferase, all with intact microsomes. The percentage latency at Vmax. decreased for PPi phosphohydrolase and for glucose 6-phosphate phosphohydrolase, but was unaffected for carbamoyl-P:glucose phosphotransferase. These observations support a tumour-related increase in translocase T2 capacity in vivo, as it transports Pi from the microsomal lumen to the medium and carbamoyl-P or PPi from the medium to the microsomal lumen.
| S-EPMC1132366 | biostudies-other
Project description:Treatment of mice bearing L1210 leukaemia with 2-difluoromethylornithine, a specific inhibitor of ornithine decarboxylase (EC 4.1.1.17), produced a profound depletion of putrescine and spermidine in the tumour cells. Sequential combination of methylglyoxal bis(guanylhydrazone), an inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), with difluoromethylornithine largely reversed the polyamine depletion and led to a marked accumulation of cadaverine in the tumour cells. Experiments carried out with the combination of difluoromethylornithine and aminoguanidine, a potent inhibitor of diamine oxidase (EC 1.4.3.6), indicated that the methylglyoxal bis(guanylhydrazone)-induced reversal of polyamine depletion was mediated by the known inhibition of diamine oxidase by the diguanidine. In spite of the normalization of the tumour cell polyamine pattern upon administration of methylglyoxal bis(guanylhydrazone) to difluoromethylornithine-treated animals, the combination of these two drugs produced a growth-inhibitory effect not achievable with either of the compounds alone.
| S-EPMC1153170 | biostudies-other
Project description:BackgroundInflammation is generally connected to tumour progression and development. The secretory phospholipase A2IIa (sPLA2IIa) is an important inflammatory enzyme that catalyse the hydrolysis of membrane phospholipids into arachidonic and lysophosphatidic acid, which are the precursors for production of a lot of pro-inflammatory mediators like prostaglandins, prostacyclins, thromboxanes, leukotrienes and platelet activating factors, which involved in the proliferation, migration, invasion, and metastasis. Therefore, investigating safe and effective sPLA2IIa inhibitors as a therapeutic agent to treat cancer is indeed in need.MethodsAnti-inflammatory function of corosolic acid was evaluated by docking it with sPLA2IIa enzyme, sPLA2IIa inhibition, calcium and substrate concentration-dependent assays; intrinsic fluorescence and UV-CD analysis; neutralisation of sPLA2IIa induced indirect hemolytic and edema. Evaluated the anticancer activity of corosolic acid by MTT assays and caspase-3 expression; the anti-tumour activity by EAC-induced cell line and interleukin 6 expression.ResultsThe corosolic acid inhibits sPLA2IIa activity to 82.21±2.82%. The inhibition was evaluated by increasing calcium from 2.5 to 15 µM and substrate from 20 to 120 nM, it did not affect the level of inhibition. Corosolic acid altered the intrinsic fluorescence and UV-CD spectra of sPLA2IIa enzyme, indicating the direct interaction. It neutralised sPLA2IIa induced hemolytic activity from 97±1.23% to 15.75±1.44% and edema from 171.51±2.39% to 119.3±2.6%. Further, as antiproliferative activity, corosolic acid reduced the PC3 cell viability from 99.66±0.57% to 23±2.64% and suppressed LPS-induced IL-6 level from 94.35±2.2% to 34.36±2.4%. It increased mean survivability time from 30 to 38 days and displayed the drug-like qualities.ConclusionAll the experimental results have proven the corosolic acid as an anti-inflammatory and anticancer molecule that may further be used to develop it as a drug.
| S-EPMC9811966 | biostudies-literature
Project description:Ehrlich ascites-tumour cells were investigated with regard to their stability to transport L-lactate by measuring either the distribution of [14C]lactate or concomitant H+ ion movements. The movement of lactate was dependent on the pH difference across the cell membrane and was electroneutral, as evidenced by an observed 1:1 antiport for OH- ions or 1:1 symport with H+ ions. 2. Kinetic experiments showed that lactate transport was saturable, with an apparent Km of approx. 4.68 mM and a Vmax. as high as 680 nmol/min per mg of protein at pH 6.2 and 37 degrees C. 3. Lactate transport exhibited a high temperature dependence (activation energy = 139 kJ/mol). 4. Lactate transport was inhibited competitively by (a) a variety of other substituted monocarboxylic acids (e.g. pyruvate, Ki = 6.3 mM), which were themselves transported, (b) the non-transportable analogues alpha-cyano-4-hydroxycinnamate (Ki = 0.5 mM), alpha-cyano-3-hydroxycinnamate (Ki = 2mM) and DL-p-hydroxyphenyl-lactate (Ki = 3.6 mM) and (c) the thiol-group reagent mersalyl (Ki = 125 muM). 5. Transport of simple monocarboxylic acids, including acetate and propionate, was insensitive to these inhibitors; they presumably cross the membrane by means of a different mechanism. 6. Experiments using saturating amounts of mersalyl as an "inhibitor stop" allowed measurements of the initial rates of net influx and of net efflux of [14C]lactate. Influx and efflux of lactate were judged to be symmetrical reactions in that they exhibited similar concentration dependence. 7. It is concluded that lactate transport in Ehrlich ascites-tumour cells is mediated by a carrier capable of transporting a number of other substituted monocarboxylic acids, but not unsubstituted short-chain aliphatic acids.
| S-EPMC1172721 | biostudies-other
Project description:Ehrlich ascites-tumour cells accumulate Ca2+ when incubated aerobically with succinate, phosphate and rotenone, as revealed by isotopic and atomic-absorption measurements. Ca2+ does not stimulate oxygen consumption by carefully prepared Ehrlich cells, but des so when the cells are placed in a hypo-osmotic medium. Neither glutamate nor malate support Ca2+ uptake in 'intact' Ehrlich cells, nor does the endogenous NAD-linked respiration. Ca2+ uptake is completely dependent on mitochondrial energy-coupling mechansims. It was an unexpected finding that maximal Ca2+ uptake supported by succinate requires rotenone, which blocks oxidation of enogenous NAD-linked substrates. Phosphate functions as co-anion for entry of Ca2+. Ca2+ uptake is also supported by extra-cellular ATP; no other nucleoside 5'-di- or tri-phosphate was active. The accumulation of Ca2+ apparently takes place in the mitochondria, since oligomycin and atractyloside inhibit ATP-supported Ca2+ uptake. Glycolysis does not support Ca2+ uptake. Neither free mitochondria released from disrupted cells nor permeability-damaged cells capable of absorbing Trypan Blue were responsible for any large fraction of the total observed energy-coupled Ca2+ uptake. The observations reported also indicate that electron flow through energy-conserving site 1 promotes Ca2+ release from Ehrlich cells and that extra-cellular ATP increase permeability of the cell membrane, allowing both ATP and Ca2+ to enter the cells more readily.
| S-EPMC1163986 | biostudies-other
Project description:Glutathione metabolism was studied in cancer cells during the growth of an Ehrlich ascites tumour. GSH, but not GSSG, content decreases when cell proliferation and the rate of protein synthesis in the tumour decrease. This change correlates with a decrease in the rate of GSH synthesis and an increase in glutathione peroxidase and glutathione S-transferase activities. Glutathione efflux from tumour cells seems to co-ordinate with the rate of GSH synthesis. Cysteine, and not methionine, promotes GSH synthesis in tumour cells. However, changes in the rate of GSH synthesis are not due to limitations in the supply of blood cysteine or to changes in the intracellular amino acid pool of the cancer cells. Our data suggest that changes in protein metabolism accompanying tumour growth in vivo can modulate glutathione content in cancer cells.
| S-EPMC1133048 | biostudies-other
Project description:We have investigated the time course of the changes in protein metabolism in skeletal muscle and liver in mice during the progression of growth of an Ehrlich ascites tumour. The rate of protein synthesis in muscle begins to fall very rapidly, and the decrease is clearly established by the time the tumour first becomes visible at 4 days after implantation of the cells. Liver protein synthesis increases substantially, and protein breakdown in muscle increases, but the onset of both these changes occurs later than the fall in muscle protein synthesis. A decrease in food intake in these animals occurs very rapidly after introduction of the cells. The fractional rate of protein synthesis in the tumour cells falls from 73%/day at 5 days to 26%/day at 12 days after injection, but on an absolute basis the rate of protein synthesis in the tumour at 5 days of growth is very small compared with that in muscle and liver. These results are consistent with the notion that the initial effects on muscle protein synthesis and food intake are brought about by humoral factors rather than as direct consequences of the metabolic demands of the growing tumour.
| S-EPMC1133644 | biostudies-other
Project description:The clinical success of the applicability of tea polyphenols awaits efficient systemic delivery and bioavailability. Herein, following the concept of nanochemoprevention, which uses nanotechnology for enhancing the efficacy of chemotherapeutic drugs, we employed tea polyphenols, namely theaflavin (TF) and epigallocatechin-3-gallate (EGCG) encapsulated in a biodegradable nanoparticulate formulation based on poly(lactide-co-glycolide) (PLGA) with approximately 26% and 18% encapsulation efficiency, respectively. It was observed that TF/EGCG encapsulated PLGA nanoparticles (NPs) offered an up to ~7-fold dose advantage when compared with bulk TF/EGCG in terms of exerting its antiproliferative effects and also enhanced the anticancer potential of cisplatin (CDDP) in A549 (lung carcinoma), HeLa (cervical carcinoma), and THP-1 (acute monocytic leukemia) cells. Cell cycle analysis revealed that TF/EGCG-NPs were more efficient than bulk TF/EGCG in sensitizing A549 cells to CDDP-induced apoptosis, with a dose advantage of up to 20-fold. Further, TF/EGCG-NPs, alone or in combination with CDDP, were more effective in inhibiting NF-κB activation and in suppressing the expression of cyclin D1, matrix metalloproteinase-9, and vascular endothelial growth factor, involved in cell proliferation, metastasis, and angiogenesis, respectively. EGCG and TF-NPs were also found to be more effective than bulk TF/EGCG in inducing the cleavage of caspase-3 and caspase-9 and Bax/Bcl2 ratio in favor of apoptosis. Further, in vivo evaluation of these NPs in combination with CDDP showed an increase in life span (P<0.05) in mice bearing Ehrlich's ascites carcinoma cells, with apparent regression of tumor volume in comparison with mice treated with bulk doses with CDDP. These results indicate that EGCG and TF-NPs have superior cancer chemosensitization activity when compared with bulk TF/EGCG.
| S-EPMC4636172 | biostudies-literature