Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutathione (GSH) levels were measured in 13 human tumor cell lines derived from carcinomas of the bladder, ovary, and colon and from melanoma and glioblastoma. High levels were found in four of five bladder cell lines. The average GSH concentration in the bladder cell lines was approximately 6-fold higher than in the non-bladder cell lines. Because this difference suggested the possibility of elevation of GSH in urothelial neoplasia, we measured GSH in bladder tumor tissue from patients with transitional cell carcinoma (TCC) of the bladder (Group I, n = 17). GSH was also measured in two types of control tissues: (a) nontumor bladder tissue from patients with TCC or a history of TCC of the bladder (Group II, n = 23); and (b) bladder tissue from patients without bladder cancer (Group III, n = 14). Thirteen sets of paired specimens of tumor and nontumor bladder tissue from the same patient were evaluated. The tissues were flash-frozen, and GSH was measured after histological assessment of the same samples. Free and total GSH (free + mixed disulfides) were measured by a high-performance liquid chromatography assay with fluorescence detection and expressed as nanomoles/mg protein. The mean free GSH (+/- SD) for groups I, II, and III was 32.0 +/-18.7, 17.3 +/- 11.4, and 9.3 +/- 4.0, respectively, and the mean total GSH was 45.9 +/- 32.5, 23.7 +/- 17.1, and 12.2 +/- 6.7. The respective differences between groups (I and II, I and III, and II and III) were statistically significant for both free and total GSH (Ps ranging from <0.0001 to </=0.05). Free and total GSH were higher in tumor than in nontumor tissue in 11 of 13 paired specimens (free, 29.5 +/- 20.4 versus 18.7 +/- 11.7, P = 0.017; total, 41.7 +/- 33.8 versus 24.9 +/- 18.4, P = 0.005). No correlation was found between GSH levels and the proportion of tumor cells in the tissue. Influence of smoking on GSH expression could not be assessed because 81% of the patients with TCC had a smoking history. Similarly, because only 11% had prior cytotoxic chemotherapy, the influence of prior cytotoxic exposure on GSH could not be assessed. The results indicate: (a) significantly higher levels of GSH in TCC compared to tumor-free bladder tissue; and (b) higher GSH levels in nontumor bladder tissue from patients with bladder cancer than from patients without TCC. The clinical implications of this work include the possibility that GSH may play a role in the resistance of bladder cancer to chemotherapy and may be associated with bladder carcinogenesis.
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PMID:Translational studies of glutathione in bladder cancer cell lines and human specimens. 981 51

Acrolein is a highly reactive unsaturated aldehyde formed endogenously and present in the environment. Acrolein efficiently reduces glutathione-contents and is highly cytotoxic in two lung carcinoma cell lines (A-427 and SK-LU-1) and the glioblastoma cell line A-172. A-427, which has the lowest GSH content of the cell lines, is also more sensitive to growth inhibition and more depleted in GSH after acrolein exposure. A-427 is also highly sensitive to docosahexaenoic acid (22:6 n-3, DHA) and acrolein potentiates the cytotoxic effect of DHA in this cell line, but not in the DHA-resistant cell lines SK-LU-1 and A-172. Surprisingly, the cytotoxic effect of acrolein was partially reversed by vitamin E, selenite and 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen, a Se-glutathione peroxidase mimic) in A-427 cells, but not in SK-LU-1 and A-172 cells. Using the TUNEL assay a strong nuclear fluorescence was observed in DHA-treated A-427 cells, indicating death by apoptosis, whereas acrolein apparently did not induce apoptosis.
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PMID:Acrolein cytotoxicity and glutathione depletion in n-3 fatty acid sensitive- and resistant human tumor cells. 1022 83

The relation between the effect of glutathione(GSH)-modulating compounds and platinum compounds (Cisplatin, Nedaplatin)-induced cytotoxicity was investigated. Pretreatment of human glioblastoma (T98G, U87MG) and glioma (KG1C) cell lines with L-buthionine-[S,R]-sulfoximine, which decrease the intracellular GSH concentration, remarkably increased their sensitivity against platinum compounds, whereas pretreatment with N-acetyl-L-cysteine, which increase the intracellular GSH concentration, only marginally protected the cells from the cytotoxic effect of platinum compounds. The results suggest that platinum compounds-induced cytotoxicity can be modified by GSH-modulating compounds in glioblastoma and glioma cell lines.
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PMID:Effect of glutathione-modulating compounds on platinum compounds-induced cytotoxicity in human glioma cell lines. 1069 65

Glioblastoma cells are highly malignant and show resistance to ionizing radiation, as well as anti-cancer drugs. This resistance to cancer therapy is often associated with a high concentration of glutathione (GSH). In this study, the effect of continuous down-regulation of gamma-glutamylcysteine synthetase (gamma-GCS) expression, a rate-limiting enzyme for GSH synthesis, on resistance to ionizing radiation and cisplatin (CDDP) was studied in T98G human glioblastoma cells. We constructed a hammerhead ribozyme against a gamma-GCS heavy subunit (gamma-GCSh) mRNA and transfected it into T98G cells. (1) The transfection of the ribozyme decreased the concentration of GSH and resulted in G1 cell cycle arrest of T98G cells. (2) The transfection of the ribozyme increased the cytotoxicity of ionizing radiation and CDDP in T98G cells. Thus, hammerhead ribozyme against gamma-GCS is suggested to have potential as a cancer gene therapy to reduce the resistance of malignant cells to ionizing radiation and anti-cancer drugs.
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PMID:Hammerhead ribozyme against gamma-glutamylcysteine synthetase attenuates resistance to ionizing radiation and cisplatin in human T98G glioblastoma cells. 1207 21

Glutathione (GSH) is a ubiquitous non-protein thiol essential for cellular homeostasis and protection. Diazenecarboxamides (diazenes) are new compounds that could, according to their biochemical properties, lower the intracellular GSH content, thus inhibiting the growth of tumour cells. In the present study we examined four such compounds: JK-914, JK-918, JK-1013 and UP-91. Their cytotoxic effect on the growth of eight human tumour cell lines (glioblastoma, cervical and laryngeal carcinoma cells, mammary carcinoma cells and four drug-resistant sublines) was determined using a modified colorimetric MTT assay. The rate of reaction of thiophenol (as a model thiol) with diazenes leading to diphenyl disulfide was established by chromatography (TLC). Reactivity of diazenes with GSH under quasi-physiological conditions was determined by NMR spectroscopy. Intracellular GSH content was examined spectrophotometrically by the procedure developed by Tietze (1969). Diazene UP-91 reduced significantly the cell survival of all eight examined cell lines, including four drug-resistant cell lines. Other diazenes did not influence the survival of tumour cells. Reaction time for quantitative conversion of thiophenol to diphenyl disulfide was shortest for diazene UP-91, which is highly consistent with high reactivity of the same diazene with GSH, observed under quasi-physiological conditions. UP-91 reduced intracellular GSH level, while other diazenes had no effect on it. Thus, diazenecarboxamides UP-91 is a potential anticancer agent that may inhibit the growth of tumour cells due to reduction in glutathione level.
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PMID:Diazenecarboxamide UP-91, a potential anticancer agent, acts by reducing cellular glutathione content. 1257 33

The mycotoxin fumonisin B1 (FB1) is produced by Fusarium verticillioides, which commonly infects corn and other agricultural products. Fusarium species are also a frequent finding in moisture-damaged buildings, causing possible human exposure to FB1. FB1 is neurotoxic and carcinogenic in a number of animal species. In this study, we have investigated the effects of FB1 on human U-118MG glioblastoma cells. The production of reactive oxygen species (ROS), lipid peroxidation, intracellular reduced glutathione (GSH) levels, cell viability, caspase-3-like protease activity and DNA fragmentation were studied in cells exposed to 0.01-100 microM FB1 for 0.5-144 h. FB1 increased lipid peroxidation and the production of ROS in U-118MG cells, showing significant effects after culture times from 48 to 144 h at dose levels of 10 or 100 microM FB1. These effects were accompanied by changes in the GSH levels and cell viability, which decreased significantly after incubating the cells for 48-144 h with the toxin. Signs of apoptosis were indicated by increased caspase-3-like protease activity and internucleosomal DNA fragmentation. Thus, oxidative stress and apoptosis may be involved in the neurotoxicity induced by FB1.
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PMID:Fumonisin B1-induced toxicity and oxidative damage in U-118MG glioblastoma cells. 1533 81

Temozolomide (TMZ) is a methylating agent with promising antitumor efficacy for the treatment of melanomas and intermediate-grade gliomas. Unfortunately, its use in the management of high-grade gliomas (glioblastomas) is limited by multifaceted resistance mechanisms. The aim of this study was to evaluate the possibility to improve the cytotoxic response of two human glioblastoma cell lines, U87MG and U373MG, to TMZ by the use of Tempol (TPL), a low molecular weight piperidine nitroxide that has been shown to inhibit in vitro and in vivo growth of murine glioma cells. To this purpose, we used two different schedules for the combined exposure to the two agents. Our data indicate that TPL synergizes with TMZ in both U87MG and U373MG cells for both schedules tested. This effect is accompanied by an increase in apoptotic cell death and by changes in the expression of genes involved in control of the apoptotic process. TPL was also observed to induce a cell-type specific decrease in GSH levels and in GSH-related enzyme activities that could contribute to its sensitizing effect.
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PMID:The piperidine nitroxide Tempol potentiates the cytotoxic effects of temozolomide in human glioblastoma cells. 1554 22

Multidrug resistance protein 1 (MRP1) is one of the representative members of the ATP-binding cassette superfamily of transporters that is involved in resistance to chemotherapeutic agents in cancer patients. MRP1 functions as an efflux pump of drugs, primarily those conjugated to glutathione (GSH). Decreases in the intracellular concentration of GSH have been shown to enhance the response of MRP1-overexpressing cells to MRP1-substrate drugs by limiting the available drug-GSH conjugates. We report here that alpha-tocopheryl succinate (TOS), a vitamin E analogue, decreased intracellular GSH concentration and blocked MRP1 function in glioblastoma cells. Functional blockade by TOS of MRP1 was confirmed by the enhanced accumulation of etoposide (VP-16), an MRP1-substrate drug. As a result, co-treatment of TOS with VP-16 or treatment with liposomes containing both TOS and VP-16 greatly enhanced the response of MRP1-expressing glioblastoma cells to VP-16. TOS may be a promising adjuvant for enhancing the therapeutic efficacy of VP-16 in patients with MRP1-expressing glioblastomas.
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PMID:Potentiation by alpha-tocopheryl succinate of the etoposide response in multidrug resistance protein 1-expressing glioblastoma cells. 1561 35

Fumonisin B1 (FB1) is a mycotoxin produced by Fusarium verticillioides, which is a common infectant of corn and other cereal grains. Of concern to human health is also a possible airborne exposure to FB1-producing strains of F. verticillioides, which may grow in moisture-damaged buildings. In this study, we have characterized oxidative stress-related parameters induced by FB1 in three different neural cell lines, human SH-SY5Y neuroblastoma, rat C6 glioblastoma and mouse GT1-7 hypothalamic cells. The cells were exposed to graded doses of FB1 between 0.1 and 100 microM for 0-144 h after which the production of reactive oxygen species (ROS), lipid peroxidation, intracellular glutathione (GSH) levels and cell viability were measured. FB1 caused a dose-dependent increase of ROS production in C6 glioblastoma and GT1-7 hypothalamic cells but was without an effect in SH-SY5Y cells. Decreased GSH levels, increased MDA-formation, indicative of lipid peroxidation and necrotic cell death were observed in all cell lines after incubation with FB1. These findings indicate that FB1 induces oxidative stress in human, rat and mouse neural cell cultures.
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PMID:Oxidative stress induced by fumonisin B1 in continuous human and rodent neural cell cultures. 1562 11

We have previously synthesized various diazenecarboxamides (subsequently referred to as diazenes) that were cytotoxic to several tumor cell lines. To increase their biological activity, the structure has been modified appropriately. In the present study we examined the effects of N(1)-phenyl-N(2)-(2-pyridinylmethyl)diazenedicarboxamide (RL-337) obtained from the previously examined cytotoxic compound N(1)-phenyl-N(2)-(2-pyridinyl)diazenecarboxamide (JK-279), and compared them with those of diazene JK-279. Using a modified colorimetric MTT assay, the cytotoxicity of RL-337 was determined on human cervical carcinoma HeLa cells, glioblastoma A1235 cells, and prostate adenocarcinoma PC-3 cells. The possible synergistic effect of diazene RL-337 with cisplatin, doxorubicin, and vincristine, and its influence on intracellular GSH content was examined on HeLa cells. Diazene RL-337 was cytotoxic against all three human tumor cell lines, being more cytotoxic to HeLa cells than diazene JK-279. The higher efficacy of RL-337 than of JK-279 can be connected with higher basicity of the 2-picoline moiety present in the former diazene comparing with the pyridine fragment that is a part of the latter. The diazene RL-337 acted synergistically with cisplatin, doxorubicin, and vincristine (diazene JK-279 exhibited synergistic effect only with cisplatin). Glutathione (determined by Tietze's method) was not a target molecule of diazene RL-337 (but was for JK-279, as shown earlier). After just 1 h treatment with diazene RL-337, the cells started to lose membrane integrity. There was no cleavage of caspase-3 in RL-337-treated samples, and the majority of cells died 6 h after the treatment through necrosis (previously, apoptosis-like cell death was detected for diazene JK-279). Thus, although diazenes JK-279 and RL-337 are very similar in their structure, they exhibit widely different biological activity.
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PMID:Structurally similar diazenes exhibit significantly different biological activity. 1646 20


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