Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study the enzyme glutaminase, purified from the ascites fluid of ovarian cancer patients, was analysed for its antiangiogenic activity. Intraperitoneal administration of this enzyme reduces the number of tumor directed capillaries in solid and ascites tumor bearing Swiss mice induced by transplantation of Ehrlich ascites cells. The enzyme has a critical role in regulating the secretion of vascular endothelial growth factor (VEGF) from tumor cell and in turn tumor growth. Glutamine analogue like 6-diazo, 5- oxo L-norleucine (DON) is also found to be effective in regulating vascular endothelial growth factor (VEGF) secretion from tumor cells in vitro. Treatment with enzyme reduced serum VEGF levels of the tumor induced animals. In vitro VEGF production by EAC cells was reduced in a concentration dependent manner in presence of glutamine analogue.
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PMID:Modulation of tumor induced angiogenesis in Ehrlich ascites tumor. 1574 40

The influence of modified antineoplaston AS2-1 (with altered ratio of L-phenylalanine and L-glutamine derivatives, "Deglutam") on the activity of glutamine synthetase, glutaminase isoforms in the carcinosarcoma SM-1, tumor weight, per cent of the inhibition of tumor growth and blood impact index was investigated in rats with carcinosarcoma SM-1. The preparation was administered in the dose of 125 mg/kg twice a day for 12 days (on the 7th day after tumor transplantation). Intensive growth of carcinosarcoma SM-1 was accompanied by activtion of the glutamine metabolizing enzymes. The dose-response effect of "Deglutam" on the studied enzymes depended on the mode of preparation administration. The intragastric administration of the preparation caused the same effect on the glutamine metabolizing of SM-1 cells; as it was earlier observed in rat liver. Administration of the modified preparation ANP AS2-1 (containing L-glutamine derivatives) influences regulation of glutamine metabolism in carcinosarcoma SM-1 cells, possibly, due to formation of substrates in the tissues of the tumor-bearing body similar to glutamine. It is also possible that in the tumor tissues these enzymes have different affinity to glutamine. This may explain greater effectiveness of the synthetic preparation on the basis of L-glutamine derivatives rather than the amino acid itself.
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PMID:[The regulatory action of dipeptide "Deglutam" on the glutamine metabolized enzymes in the carcinosarcoma SM-1 cells]. 1585 Feb 18

Mitochondrial glutathione (mtGSH) depletion increases sensitivity of Bcl-2-overexpressing B16 melanoma (B16M)-F10 cells (high metastatic potential) to tumor necrosis factor-alpha (TNF-alpha)-induced oxidative stress and death in vitro. In vivo, mtGSH depletion in B16M-F10 cells was achieved by feeding mice (where the B16M-F10 grew as a solid tumor in the footpad) with an L-glutamine (L-Gln)-enriched diet, which promoted in the tumor cells an increase in glutaminase activity, accumulation of cytosolic L-glutamate, and competitive inhibition of GSH transport into mitochondria. L-Gln-adapted B16M-F10 cells, isolated using anti-Met-72 monoclonal antibodies and flow cytometry-coupled cell sorting, were injected into the portal vein to produce hepatic metastases. In l-Gln-adapted invasive (iB16M-Gln+) cells, isolated from the liver by the same methodology and treated with TNF-alpha and an antisense Bcl-2 oligodeoxynucleotide, viability decreased to approximately 12%. iB16M-Gln+ cell death associated with increased generation of O2*- and H2O2, opening of the mitochondrial permeability transition pore complex, and release of proapoptotic molecular signals. Activation of cell death mechanisms was prevented by GSH ester-induced mtGSH replenishment. The oxidative stress-resistant survivors showed an adaptive response that includes overexpression of manganese-containing superoxide dismutase (Mn-SOD) and catalase activities. By treating iB16M-Gln+ cells with a double anti- antisense therapy (Bcl-2 and SOD2 antisense oligodeoxynucleotides) and TNF-alpha, metastatic cell survival decreased to approximately 1%. Chemotherapy (taxol plus daunorubicin) easily removed this minimum percentage of survivors. This contribution identifies critical molecules that can be sequentially targeted to facilitate elimination of highly resistant metastatic cells.
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PMID:Bcl-2 and Mn-SOD antisense oligodeoxynucleotides and a glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-alpha and chemotherapy. 1626 11

Ehrlich ascites tumor cells (EATC) is a highly proliferative malignant cell line derived from mouse mammary epithelia, whereas their derivative, 0.28AS-2 cells, expressing antisense glutaminase mRNA, show a less transformed phenotype and loss of their tumorigenic capacity in vivo correlated with an inhibition of glutaminase expression. The mRNA differential display technique was applied to these two cell lines for the identification and isolation of genes whose transcription was altered. Side-by-side comparisons of cDNA patterns among relevant RNA samples revealed four genes significantly downregulated in 0.28AS-2 cells: high-mobility group Hmga2 protein, Fmnl3 or formin-like protein 3, Nedd-4 ubiquitin-protein ligase, and ubiquitin carboxyl-terminal hydrolase Usp-15. These positives were confirmed by Northern analysis. The four targeted genes have relevant functions in cell growth and proliferation. Our results show the validity of mRNA differential display technique to get insights into the molecular mechanisms underlying the acquisition of a more differentiated phenotype by tumor cells after inhibition of glutaminase expression.
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PMID:Identification of genes downregulated in tumor cells expressing antisense glutaminase mRNA by differential display. 1629 18

Treatment for metastatic melanoma has mostly been unsatisfactory despite advances in ongoing medical research. Here we investigated the role of acivicin, a glutamine analogue, singly and in combination with either E. coli glutaminase or cisplatin, on the growth, angiogenic activity and invasiveness of B16F10 cells in vitro and after allografting in C57BL/6 mice. B16F10 melanoma colonization in the lungs of mice was measured by monitoring colony counts. Host toxicity was assessed with reference to tumor bearing host's weight and survivability. Acivicin promoted melanoma dormancy and reduced melanoma associated angiogenic factors like VEGF level and vessel diameter. Acivicin in combination with glutaminase significantly suppressed tumor growth by 66.7% and increased life-span by 43.5% without host toxicity. Tumor VEGF content was significantly lowered by combination therapy as assessed by ELISA. Accelerated cytotoxicity, reduced invasion and enhanced apoptosis of melanoma cells were exhibited in vitro by combined than by single agent treatment. Moreover, invasion of melanoma cells through matrigel chambers was reduced in presence of acivicin and glutaminase combination. These findings support future studies of acivicin in combination with other anticancer agents for prevention of melanoma metastasis.
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PMID:Modulation of metastatic potential of B16F10 melanoma cells by acivicin: synergistic action of glutaminase and potentiation of cisplatin cytotoxicity. 1769 51

Cellular senescence is now recognized as an important mechanism of tumor suppression, and the accumulation of senescent cells may contribute to the aging of various human tissues. Alterations of the cellular energy metabolism are considered key events in tumorigenesis and are also known to play an important role for aging processes in lower eukaryotic model systems. In this study, we addressed senescence-associated changes in the energy metabolism of human endothelial cells, using the HUVEC model of in vitro senescence. We observed a drastic reduction in cellular ATP levels in senescent endothelial cells. Although consumption of glucose and production of lactate significantly increased in senescent cells, no correlation was found between both metabolite conversion rates, neither in young endothelial cells nor in the senescent cells, which indicates that glycolysis is not the main energy source in HUVEC. On the other hand, glutamine consumption was increased in senescent HUVEC and inhibition of glutaminolysis by DON, a specific inhibitor of glutaminase, led to a significant reduction in the proliferative capacity of both early passage and late passage cells. Moreover, inhibition of glutaminase activity induced a senescent-like phenotype in young HUVEC within two passages. Together, the data indicate that glutaminolysis is an important energy source in endothelial cells and that alterations in this pathway play a role in endothelial cell senescence.
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PMID:Premature senescence of human endothelial cells induced by inhibition of glutaminase. 1831 46

Malignancy depletes host glutathione (GSH) levels to increase treatment-related toxicity and increases itself to resist the treatments. Our previous studies have shown that dietary glutamine (GLN) prevented 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors through enhancing gut GSH release and reducing tumor GSH level. In addition, GSH synthesis, metabolism, and recycling are accomplished in gamma-glutamyl cycle. We hypothesized that the GLN prevention might be through a differential regulation of the gamma-glutamyl cycle enzymes. Female Sprague-Dawley rats were randomized into DMBA-tumor bearing, DMBA-treated, and control groups subdivided into GLN and water groups. GLN supplementation was given at 1 g/kg/day by gastric gavage. The activities and messenger RNA levels of gamma-glutamyl transpeptidase (GTP), gamma-glutamylcysteine synthetase (GCS), 5-oxo-L-prolinase (OPase), gamma-glutamyl transferase (GTF), and glutaminase (GLNase) were determined in gut mucosa and breast tumor using specific enzyme assays and semiquantitative reverse transcription polymerase chain reaction. GLN upregulated gut GTP, GCS, OPase, and GLNase in DMBA-tumor bearing, DMBA-treated, and/or control rats; however, it downregulated these enzymes in the tumor. The paradoxical effect of GLN on key GSH recycling enzymes in the gut versus tumor suggests that dietary supplemental GLN could be used in the clinical practice to increase the therapeutic index of cancer treatments by protecting normal tissues from, and sensitizing tumor cells to, chemotherapy and radiation-related injury.
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PMID:Glutamine affects glutathione recycling enzymes in a DMBA-induced breast cancer model. 1858 86

Dynamic nuclear polarization (DNP) is an emerging technique for increasing the sensitivity of (13)C MR spectroscopy (MRS). [5-(13)C(1)]Glutamine was hyperpolarized using this technique by up to 5%, representing a 6000-fold increase in sensitivity. The conversion of hyperpolarized glutamine to glutamate by mitochondrial glutaminase was demonstrated using (13)C-MRS measurements in cultured human hepatoma cells (HepG2). These results represent the first step in developing an imaging technique for detecting glutamine metabolism in vivo. Furthermore, since glutamine utilization has been correlated with cell proliferation, the study suggests a new technique for detecting changes in tumor cell proliferation.
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PMID:13C MR spectroscopy measurements of glutaminase activity in human hepatocellular carcinoma cells using hyperpolarized 13C-labeled glutamine. 1866 4

Tumor cells intensely utilize glutamine as the major source of respiratory fuel. Glutamine-analogue acivicin inhibits tumor growth and tumor-induced angiogenesis in Ehrlich ascites carcinoma. In the present study, antitumor properties of acivicin in combination with glutaminase enzyme is reported. Acivicin along with E. coli glutaminase synergistically reduced in vitro proliferation and matrigel invasion of human MCF-7 and OAW-42 cells. Effects of single and combined treatments with acivicin and glutaminase on angiogenic factors were also analyzed in these cell lines. Co-administration of the treatment agents inhibits the release of VEGF and MMP-9 by cells in culture supernatant significantly than single agent treatments. The result suggests that combination of acivicin with glutaminase may provide a better therapeutic option than either of them given separately for treating human breast and ovarian cancer. However, further studies are required to be conducted in vivo for its confirmation.
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PMID:Acivicin with glutaminase regulates proliferation and invasion of human MCF-7 and OAW-42 cells--an in vitro study. 1869 67

Glutamine is an important source of energy for neoplastic tissues, and products of its metabolism include, among others, glutamate (Glu) and glutathione (GSH), the two molecules that play a key role in tumor proliferation, invasiveness and resistance to therapy. Glutamine hydrolysis in normal and transforming mammalian tissues alike, is carried out by different isoforms of glutaminases, of which the two major are liver-type glutaminase (LGA) and kidney-type glutaminase (KGA). This brief review summarizes available data on the expression profiles and activities of these isoenzymes in different neoplastic tissues as compared to the tissues of origin, and dwells on recent work demonstrating effects of manipulation of glutaminase expression on tumor growth. A comment is devoted to the emerging evidence that LGA, apart from degrading Gln for metabolic purposes, is involved in gene transcription; its enforced overexpression in glioma cells was found to reduce their proliferation and migration.
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PMID:Glutamine in neoplastic cells: focus on the expression and roles of glutaminases. 1942 9


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