Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Contrary to bacterial DNA, mammalian DNA contains very little if any N(6)-methyldeoxyadenosine (MDA). The possible biological effect of this nucleoside on eukaryotic cells has been studied on different tumor cell lines. Addition of MDA to C6.9 glioma cells triggers a differentiation process and the expression of the oligodendroglial marker 2',3'-cyclic nucleotide 3'phosphorylase (CNP). The biological effects of N(6)-methyldeoxyadenosine were not restricted to C6.9 glioma cells since differentiation was also observed on pheochromocytoma and teratocarcinoma cell lines and on dysembryoplastic neuroepithelial tumor cells. The precise mechanism by which MDA induces cell differentiation remains unclear, but is related to cell cycle modifications. These data point out the potential interest of N(6)-methyldeoxyadenosine as a novel antitumoral and differentiation agent. They also raise the intriguing question of the loss of adenine methylation in mammalian DNA. Furthermore, the finding that a methylated nucleoside found in bacterial DNA induces a biological process might have implications in gene therapy approaches when plasmid DNAs are injected into humans.
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PMID:The bacterial nucleoside N(6)-methyldeoxyadenosine induces the differentiation of mammalian tumor cells. 1145 63

In spite of extensive research in molecular carcinogenesis, genes that can be considered primary targets in human carcinogenesis remain to be identified. Mutated oncogenes or cellular growth regulatory genes, when incorporated into normal human epithelial cells, failed to immortalize or transform these cells. Therefore, they may be secondary events in human carcinogenesis. Based on some experimental studies we have proposed that downregulation of a differentiation gene may be the primary event in human carcinogenesis. Such a gene could be referred to as a tumor-initiating gene. Downregulation of a differentiation gene can be accomplished by a mutation in the differentiation gene, by activation of differentiation suppressor genes, and by inactivation of tumor suppressor genes. Downregulation of a differentiation gene can lead to immortalization of normal cells. Mutations in cellular proto-oncogenes, growth regulatory genes, and tumor suppressor genes in immortalized cells can lead to transformation. Such genes could be called tumor-promoting genes. This hypothesis can be documented by experiments published on differentiation of neuroblastoma (NB) cells in culture. The fact that terminal differentiation can be induced in NB cells by adenosine 3',5'-cyclic monophosphate (cAMP) suggests that the differentiation gene in these cells is not mutated, and thus can be activated by an appropriate agent. The fact that cAMP-resistant cells exist in NB cell populations suggests that a differentiation gene is mutated in these cancer cells, or that differentiation regulatory genes have become unresponsive to cAMP. In addition to cAMP, several other differentiating agents have been identified. Our proposed hypothesis of carcinogenesis can also be applied to other human tumors such as melanoma, pheochromocytoma, medulloblastoma, glioma, sarcoma, and colon cancer.
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PMID:Differentiation genes: are they primary targets for human carcinogenesis? 1156 2

The known effects of nerve growth factor (NGF) are induction of differentiation and promotion of survival. We analysed the effects of exogenously added NGF on rat C6 and 9L glioma cells and the rat pheochromocytoma cell line PC12. Cells were seeded into 96-well plates and exposed to different concentrations of FCS (10%, 5%, 1%, 0.5% and no FCS) supplemented with or without 50 ng/ml NGF for up to 120 hours. Cell survival was measured using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-assay. In this study we could clearly show two different effects: (1) proliferation was not influenced by NGF under high, medium or low serum and (2) survival rates increased under dramatic or complete serum deprivation, indicating that NGF acts as survival factor against cell death or cell cytostasis.
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PMID:NGF increases cell survival rates under serum deprived conditions. 1172 57

Central Glia-4 (CG-4) glioma cells exhibit Na(+)-dependent glutamate uptake, and mRNA for each of the GLT, GLAST, and EAAC glutamate transporters was found in the cells by RT-PCR. However, GLT protein in CG-4 cells was not detected by Western blotting. The Wnt-1 oncogene markedly decreased the expression of the mRNAs for GLT and GLAST glutamate transporters in CG-4 glioma cells. This effect of Wnt-1 is in direct contrast to its previously published effects on C6 astrocytoma cells where Wnt-1 induces the expression of GLT, but not protein, and on PC12 pheochromocytoma cells where Wnt-1 induces GLAST. We suggest that these differences in the ability of Wnt-1 to induce or repress GLT and GLAST are due to differences in Wnt-1 dosages or Wnt-1-induced signaling pathways in these cells. The abnormal translation of the GLT RNA in Wnt-1-expressing C6 cells was ascribed to some abnormality in the processing of the GLT transcript. Consistent with this idea is the finding that GLT mRNA was translated in Wnt-1-expressing C6 cells when the GLT mRNA required no splicing before translation occurred.
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PMID:Wnt-1 has multiple effects on the expression of glutamate transporters. 1247 Jul 8

4-Hexylresorcinol, which is used as an anthelmintic and antiseptic, was nominated by the National Cancer Institute for study. Toxicology and carcinogenesis studies were conducted by administering 4-hexylresorcinol (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Sixteen-Day and Thirteen-Week Studies: In the 16-day studies, groups of five rats and five mice of each sex were administered 0, 31.3, 62.5, 125, 250, or 500 mg/kg 4-hexylresorcinol. Survival was not affected. Decreased body weights were seen in male rats that received 250 or 500 mg/kg 4-hexylresorcinol. No other effects were observed. In the 13-week studies, groups of 10 rats and 10 mice of each sex were administered 0, 62.5, 125, 250, 500, or 1,000 mg/kg of the chemical, 5 days per week. All rats and male mice and 9/10 female mice that received 1,000 mg/kg died before the end of the studies. Final mean body weights of male rats that received 250 or 500 mg/kg were 22% or 38% lower than that of the vehicle controls; final mean body weights of female rats that received 250 or 500 mg/kg were 16% or 9% lower. No compound-related gross or microscopic pathologic effects were observed in rats. No body weight effects were observed for mice. Mild to moderate nephropathy was dose related in male and female mice. Based on these results, 2-year toxicology and carcinogenesis studies of 4-hexylresorcinol were conducted by administering 0, 62.5, or 125 mg/kg to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 7%-11% lower than those of the vehicle controls throughout the study. Mean body weights of low dose male and dosed female rats were similar to those of the vehicle controls. The body weights of dosed male and dosed female mice were comparable to those of vehicle controls except during the last 16 weeks of the studies, when body weights were 6%-16% lower in the dosed groups. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: vehicle control, 30/50; low dose, 29/50; high dose, 33/50; female rats: 28/50; 32/50; 30/50; male mice: 36/50; 26/50; 30/50; female mice: 35/50; 32/50; 35/50). Nonneoplastic and Neoplastic Lesions in the Two-Year Studies: Two astrocytomas and an oligodendroglioma were observed in high dose male rats, a glioma was observed in one low dose male rat, and an oligodendroglioma was observed in one vehicle control male rat. These neoplasms were not considered to be related to 4-hexylresorcinol administration. Focal medullary hyperplasia of the adrenal gland was observed at increased incidences in dosed male mice (5/50; 16/50; 10/49). Pheochromocytomas in male mice occurred with a marginal upward trend (1/50; 2/50; 5/49). Historically, these neoplasms are observed in about 1% of corn oil vehicle control B6C3F1 male mice. The incidences of neoplasms of the harderian gland in male mice were slightly increased over those in the vehicle controls (adenomas or carcinomas, combined: 0/50; 4/50; 3/50). Decreases were observed in the incidences of mononuclear cell leukemia in dosed male (12/49; 7/50; 1/50) and female (16/50; 3/50; 2/50) rats, hepatocellular adenomas or carcinomas (combined) in dosed male mice (21/50; 9/50; 9/50), and circulatory system tumors in male (10/50; 4/50; 2/50) and female (6/50; 2/49; 0/50) mice. These decreased incidences of tumors in rats and mice are considered to be possibly related to 4-hexylresorcinol administration. The incidences and severity of nephropathy (male: 39/50; 43/50; 47/50; female: 7/50; 40/49; 47/50) and incidences of osteosclerosis (male: 5/50; 5/50; 15/50; female: 21/50; 25/49; 40/50) were increased in both dosed male and female mice and are considered to be related to chemical exposure. Genetic Toxicology: 4-Hexylresorcinol was not mutagenic for Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylre, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylresorcinol induced forward mutations at the TK locus in mouse L5178Y cells in the presence of S9; no response was observed in the absence of metabolic activation. In cytogenetic assays with cultured Chinese hamster ovary (CHO) cells, 4-hexylresorcinol caused an increase in the frequency of sister chromatid exchanges (SCEs) in the absence of metabolic activation; no induction of SCEs was observed in the presence of S9. Chromosomal aberrations were not induced in CHO cells with or without metabolic activation. Data Audit: The data, documents, and pathology materials from the 2-year studies of 4-hexylresorcinol were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented appropriately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 4-hexylresorcinol for male or female F344/N rats given doses of 62.5 or 125 mg/kg. There was equivocal evidence of carcinogenic activity of 4-hexylresorcinol for male B6C3F1 mice, as shown by marginally increased incidences of pheochromocytomas (and hyperplasia) of the adrenal medulla and of harderian gland neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given doses of 62.5 or 125 mg/kg 4-hexylresorcinol. Decreased incidences of three tumors types were considered related to 4-hexylresorcinol administration: mononuclear cell leukemia in male and female rats, hepatocellular neoplasms in male mice, and circulatory system tumors in male and female mice. Synonyms: 4-hexyl-1,3-benzenediol; 4-hexyl-1,3-dihydroxybenzene
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PMID:NTP Toxicology and Carcinogenesis Studies of 4-Hexylresorcinol (CAS No. 136-77-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 6

Propyl gallate is a white to nearly white odorless powder having a slightly bitter taste. Solutions of propyl gallate turn dark in the presence of iron or iron salts. Propyl gallate has been used since 1948 as an antioxidant to stabilize cosmetics, food packaging materials, and foods containing fats. As an additive, it may be found in edible fats, oils, mayonnaise, shortening, baked goods, candy, dried meat, fresh pork sausage, and dried milk, and it is used in hair grooming products, pressure-sensitive adhesives, lubricating oil additives, and transforming oils. A NTP Carcinogenesis bioassay of propyl gallate was conducted by feeding diets containing 6,000 or 12,000 ppm propyl gallate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 untreated rats and 50 untreated mice of each sex served as controls. Survival of rats and mice was not adversely affected by propyl gallate, but mean body weights of dosed rats and mice of each sex were lower than those of the controls. At 104 weeks, mean body weights of low-and high-dose rats were 4% and 8% lower than those of the controls for males and 11% and 19% lower than those of the controls for females. Similarly, mean body weights of low-and high-dose mice were 5% and 8% lower than those of the controls for males and 11% (both dose groups) lower than those of the controls for females. Thyroid follicular-cell adenomas or carcinomas (combined) occurred in male rats with a statistically significant (P<0.05) positive trend, but the incidences in the dosed groups were not statistically significant in direct comparisons with the control groups. Moreover, the incidence of high-dose male rats with follicular-cell tumors (3/50, 6%) was not statistically different from the historical control rate (14/584, 2.4%) for the laboratory that conducted this bioassay. Rare tumors (an astrocytoma or a glioma) were found in the brains of two low-dose female rats. The incidence of all brain tumors in the Bioassay Program is only 0.86%. The absence of this tumor in the high-dose female rat group reduces the likelihood that this tumor is related to propyl gallate administration. Increased incidences of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate were observed in dosed male rats. These findings were considered to be related to administration of propyl gallate. Tumors (mostly benign) of the preputial gland, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal gland were observed with significantly (P<0.05) higher incidences in the low- dose male rats, but there was little evidence of an effect in the high-dose group. The incidences of male rats with tumors of the preputial gland were 1/50 (2%) for controls, 8/50 (16%) for the low-dose, and 0/50 (0%) for the high-dose group. Islet-cell tumors of the pancreas occurred in 2/50 (4%) control males, 9/50 (18%) low-dose males, and 4/50 (8%) for high-dose males. Pheochromocytomas of the adrenal gland were observed in 4/50 (8%) control males, 13/48 (25%) low-dose males, and 8/50 (16%) high-dose males. Negative trends (P<0.05) were observed for leukemia in male rats (16/50, 7/50, 6/50) and for fibroadenomas of the mammary gland in female rats (11/50, 2/50, 5/50). In male mice, malignant lymphoma was observed with a significantly (P</=0.014) positive trend (control, 1/50, 2%; low-dose, 3/49, 6%; high-dose, 8/50, 16%), and the incidence in the high-dose group was significantly (P</=0.028) higher than that observed in the concurrent controls. However, the high-dose incidence was not statistically different from the historical rate (60/640, 9.4%) for the laboratory that conducted this bioassay. Adenomas of the liver in female mice occurred with a statistically significant (P</=0.022) positive trend, and the incidence in the high-dose group was significantly (P</=0.039) higher than that of the controls (0/50, 0%; 2/50, 4%; 5/49, 10%). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6%; 3/50, 6%; 5/49, 10%). Negative&percnt;; 2/50, 4&percnt;; 5/49, 10&percnt;). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6&percnt;; 3/50, 6&percnt;; 5/49, 10&percnt;). Negative trends (P&lt;0.05) were obtained for fibromas of the skin or subcutaneous tissue in male mice (5/50, 1/49, 0/50). Under the conditions of this bioassay, propyl gallate was not considered carcinogenic for F344/N rats, although there was evidence of an increased proportion of low-dose male rats with preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal glands; rare tumors of the brain occurred in two low-dose females. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice of either sex, although the increased incidence of malignant lymphoma in male mice may have been related to the dietary administration of propyl gallate. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Equivocal Female Mice: Negative Synonyms: 2,4,5 trihydroxybenzoic acid propyl ester; gallic acid propyl ester; Progallin P; Tennox PG
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PMID:NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study). 1275 Jul 52

Experimental infection of BALB/c mice with the gram-positive bacterium Nocardia asteroides produces marked loss of nigrostriatal dopamine neurons, resulting in striatal dopamine depletion. To investigate the mechanism(s) responsible for this neuronal loss, we evaluated the influence of N. asteroides cell-free culture filtrates on rat pheochromocytoma PC12 cells, an in vitro model for dopamine neurons. Changes in cell viability and cell numbers were minimal after 24 h, but increased with longer incubation. In contrast, dopamine depletion occurred after 30 min incubation, and was greater with GUH-2 filtrate than with filtrate from the less virulent strain 10905. Incubation with the culture filtrate decreased viability in neuroblastoma and glioma cell lines, indicating that cytotoxic effects were not limited to dopaminergic cells. These findings suggest that the loss of nigrostriatal dopamine neurons and concomitant striatal dopamine depletion in Nocardia-infected mice may be due, at least in part, to the neurotoxicity of nocardial secretory products.
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PMID:Nocardia asteroides culture filtrates cause dopamine depletion and cytotoxicity in PC12 cells. 1293 58

The p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor receptor superfamily, facilitates apoptosis during development and after injury to the CNS. The signaling cascades activated by p75NTR that result in apoptosis remain poorly understood. In this study, we show that overexpression of p75NTR in primary cortical neurons, in pheochromocytoma cell line (PC12) cells, and in glioma cells results in activation of Jun kinase (JNK), accumulation of cytochrome c within the cytosol, and activation of caspases 9, 6, and 3. To link p75NTR-dependent JNK activation to mitochondrial cytochrome c release, regulation of BH3-domain-only family members was examined. Transcription of BH3-domain-only family members was not induced by p75NTR, but p75NTR-dependent JNK activation resulted in phosphorylation and oligomerization of the BH3-domain-only family member Bad. Loss of function experiments using Bad dominant negatives or RNA interference demonstrated a requirement for Bad in p75NTR-induced apoptosis. Together, these studies provide the first data linking apoptosis induced by p75NTR to the phosphorylation of BH3-domain-only family members.
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PMID:Apoptosis induced by p75NTR overexpression requires Jun kinase-dependent phosphorylation of Bad. 1467 1

In kidney, the Na,K-ATPase is associated with a single span protein, the gamma subunit (FXYD2). Two splice variants are differentially expressed along the nephron and have a differential influence on Na,K-ATPase when stably expressed in mammalian cells in culture. Here we used a combination of gene induction and gene silencing techniques to test the functional impact of gamma by means other than transfection. NRK-52E cells (of proximal tubule origin) do not express gamma as a protein under regular tissue culture conditions. However, when they were exposed to hyperosmotic medium, induction of only the gammaa splice variant was observed, which was accompanied by a reduction in the rate of cell division. Kinetic analysis of stable enzyme properties from control (alpha1beta1) and hypertonicity-treated cultures (alpha1beta1gammaa) revealed a significant reduction (up to 60%) of Na,K-ATPase activity measured under V(max) conditions with little or no change in the amounts of alpha1beta1. This effect as well as the reduction in cell growth rate was practically abolished when gamma expression was knocked down using specific small interfering RNA duplexes. Surprisingly, a similar induction of endogenous gammaa because of hypertonicity was seen in rat cell lines of other than renal origin: C6 (glioma), PC12 (pheochromocytoma), and L6 (myoblasts). Furthermore, exposure of NRK-52E cells to other stress inducers such as heat shock, exogenous oxidation, and chemical stress also resulted in a selective induction of gammaa. Taken together, the data imply that induction of gammaa may have adaptive value by being a part of a general cellular response to genotoxic stress.
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PMID:Stress-induced expression of the gamma subunit (FXYD2) modulates Na,K-ATPase activity and cell growth. 1528 Mar 68

Adrenomedullin is a vasoactive peptide that is upregulated in higher-grade gliomas and promotes tumor cell proliferation. Since reduced activity of the anti-oncogene PTEN seems to also correlate with higher tumor grade, this suggests an inverse association between PTEN activity and adrenomedullin expression. PC12 pheochromocytoma and human U251 glioma cell lines were stably transfected with human PTEN or control plasmid. Adrenomedullin expression was analyzed using quantitative PCR and Western blotting. A cell proliferation assay was used to assess adrenomedullin effects on U251 cells overexpressing PTEN. PC12 and U251 cells overexpressing PTEN had 17- and 8-fold decreases in adrenomedullin mRNA levels, respectively, compared to control cells. Cellular and secreted adrenomedullin peptide was similarly reduced. Addition of adrenomedullin to medium of controlled cells induced proliferation, as described previously, but U251 cells overexpressing PTEN did not respond to exogenous adrenomedullin. Further exploration revealed that PTEN also inhibits expression of the gliomas receptor for adrenomedullin, which accounts for this effect. These data were all replicated with an inducible PTEN construct confirming that these effects are not exclusively secondary to chronic overexpression. Given the profound effects of adrenomedullin on tumor cells, this is a novel and previously unidentified mechanism by which alterations in PTEN levels or function may influence tumor growth.
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PMID:PTEN inhibits adrenomedullin expression and function in brain tumor cells. 1682 Oct 90


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