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)

The effect of tamoxifen on Ca(2+) signaling and viability in Madin Darby canine kidney (MDCK) cells was investigated by using fura-2 as a Ca(2+) probe. Tamoxifen evoked a rise in cytosolic free Ca(2+) levels ([Ca(2+)](i)) concentration-dependently between 1 and 50 microM with an EC50 of 10 microM. The response was decreased by extracellular Ca(2+) removal. In Ca(2+)-free medium, pretreatment with 5 microM tamoxifen abolished the [Ca(2+)](i) increase induced by the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (1 microM), but pretreatment with brefeldin A (50 microM; a Ca(2+) mobilizer of the Golgi complex), thapsigargin (an inhibitor of the endoplasmic reticulum Ca(2+) pump), and carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler), only partly inhibited tamoxifen-induced [Ca(2+)](i) increases. This suggests that tamoxifen released Ca(2+) from multiple pools. Addition of 3 mM Ca(2+) induced a [Ca(2+)](i) rise after pretreatment with 5 microM tamoxifen in Ca(2+)-free medium. Inhibiting inositol 1,4,5-trisphosphate formation with the phospholipase C inhibitor U73122 (2 microM) did not alter 5 microM tamoxifen-induced Ca(2+) release. The [Ca(2+)](i) increase induced by 5 microM tamoxifen was not altered by La(3+), nifedipine, verapamil, or diltiazem. Tamoxifen (1-10 microM) decreased cell viability in a concentration- and time-dependent manner. Tamoxifen (5 microM) also increased [Ca(2+)](i) in neutrophils, bladder cancer cells, and prostate cancer cells from humans and glioma cells from rats. Collectively, it was found that tamoxifen increased [Ca(2+)](i) in MDCK cells by releasing Ca(2+) from multiple Ca(2+) stores in a manner independent of the production of inositol 1,4, 5-trisphosphate and also by triggering Ca(2+) influx from extracellular space. The [Ca(2+)](i) increase was accompanied by cytotoxicity.
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PMID:Dual effect of tamoxifen, an anti-breast-cancer drug, on intracellular Ca(2+) and cytotoxicity in intact cells. 1100 Jan

The antiestrogen tamoxifen is commonly used to treat breast cancer, but it also has therapeutic activity in several other types of cancer. Many of these tumors, including malignant gliomas, are estrogen receptor negative. Nonetheless, high concentrations of tamoxifen can directly reduce cell proliferation in some of these tumors and induce apoptosis. In this study, the role of tamoxifen in calcium signaling and calcium-induced cell death was studied in both malignant glioma cell lines and MCF-7 breast cancer cells. Tamoxifen potently increased the spatial expansion of calcium waves by 30-150% while significantly enhancing and prolonging agonist-induced calcium elevations. Furthermore, tamoxifen pretreatment accelerated calcium ionophore-induced death by more than 20 min, suggesting that tamoxifen lowered cellular resistance to calcium loads. In contrast to its potentiating of calcium signaling in tumors, tamoxifen had no significant effect on calcium signaling in cultures of primary astrocytes from either human or rat brain. This study demonstrates the existence of calcium signaling in breast cancer and glioma cells and identifies tamoxifen as a potential modulator of tumor-associated calcium signaling.
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PMID:Tamoxifen-induced enhancement of calcium signaling in glioma and MCF-7 breast cancer cells. 1103 78

The effects of tamoxifen, an antiestrogen, on the inhibition of protein tyrosine phosphorylation in neu/c-erbB-2 receptor, DNA synthesis and proliferation were evaluated using the malignant glioma cell lines U25 IMG and T98G which overexpressing neu/c-erbB-2. Pretreatment of two cell lines with tamoxifen resulted in a dose dependent inhibition of tyrosine phosphorylation as well as DNA synthesis and cell growth in two cell lines correlatively. The results support the hypothesis that activated protein tyrosine kinase receptors are involved in the proliferation of glioma cells. Tamoxifen may be useful in the treatment of malignant glioma.
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PMID:Tamoxifen interacts with NEU/C-ERBB-2 receptor and inhibits growth of human malignant glioma cell lines. 1172 74

We tested the hypothesis that Tamoxifen (TMX), an inhibitor of protein kinase C (PKC), augments the cytotoxicity of photodynamic therapy (PDT) treatment of human (U87) and (U25ln) glioma cells. U87 and U25ln glioma cells were plated and treated with PDT using Photofrin as the sensitizer. Cells were treated with Photofrin at various doses and with various optical (632 nm) irradiation intensities 24 h later. Cells were also treated with Photofrin at a fixed dose alone and with various doses of Tamoxifen and subjected to laser treatment 24 h later. Tumor response was tested using the (3-94,5-dimethyl-2-yl)-2,5-diphenyl-tetrazolium (MTT) method. Total toxicity of U87 cells was achieved with PDT at all doses of Photofrin (1, 2.5, 5, 10 microg/ml) with irradiation densities equal to or greater than 200 mJ/cm2. Using an irradiation intensity of 100 mJ/cm2, U87 and U25ln cells were killed in a Photofrin dose-dependent manner. Significant cytotoxicity was detected with Photofrin doses of 5 microg/ml (p < 0.05) and 10 microg/ml (p < 0.001). Tamoxifen at a dose of 500 microg/ml and higher, significantly increased the toxicity of the PDT response with 5 microg/ml Photofrin and 100 mJ/cm2 (p < 0.05). In summary, our data demonstrate that Tamoxifen significantly enhances the Photofrin PDT activity of U87 and U25ln human glioma cells.
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PMID:Tamoxifen increases photodynamic therapeutic response of U87 and U25ln human glioma cells. 1194 27

Tamoxifen, a non-steroidal anti-estrogen widely used against breast cancer, is also useful for treatment of other malignancies, due to its sensitizing effect on other chemotherapeutic agents and radiation. We have investigated the advantages of combining tamoxifen with one of the commonly used cancer chemotherapeutic drug, etoposide (VP-16) in brain tumor cell lines. While tamoxifen (10 microM) increased etoposide cytotoxicity 8.3-fold in the human glioma cell line (HTB-14), it increased etoposide cytotoxicity 47.5- and 40-fold in two primary cell lines established from pediatric medulloblastoma patients (MCH-BT-31 and MCH-BT-39), respectively. Similarly, in the pediatric ependymoma cell lines (MCH-BT-30 and MCH-BT-52), tamoxifen enhanced etoposide cytotoxicity 6- and 2.68-fold, respectively. CalcuSyn analysis of cytotoxicity data showed that tamoxifen and etoposide combinations were synergistic with combination index values ranging from 0.243 to 0.369 at IC50 level among different pediatric brain tumor cell lines. Tamoxifen is also cytotoxic at higher concentrations (> 20 microM) in brain tumor cells. To understand the mechanism underlying the tamoxifen modulation of etoposide cytotoxicity, we analyzed expression of P-glycoprotein (P-gp), insulin-like growth factor-I receptor (IGF-IR), IGF-I, IGF-II and estrogen receptor as well as protein kinase C (PKC) activity. While P-gp, IGF-IR and IGF-I were not affected, enhanced inhibition of PKC, and IGF-II were observed in brain tumor cells treated with tamoxifen and etoposide combination as compared to cells treated with either drug alone. Tamoxifen at 10 microM when combined with etoposide at 0-100 microM concentrations reduced PKC activity 77% compared to only 58% without tamoxifen. IGF-II expression decreased to 48.6% of the untreated control in the combination treatment as compared to 31.2% for etoposide alone and 26.2% for tamoxifen alone treatments. These results suggest that inhibitory effect of tamoxifen on brain tumor cells manifest through different mechanisms involving inhibition of targets such as PKC and IGF-II.
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PMID:Tamoxifen modulation of etoposide cytotoxicity involves inhibition of protein kinase C activity and insulin-like growth factor II expression in brain tumor cells. 1507 44

The antitumoral activity of nonsteroidal antiestrogens on C6 and low passage of human glioma cells was investigated. Tamoxifen and its metabolite, 4-hydroxytamoxifen, did not influence viability of the human cells, but tamoxifen had a limited antiproliferative effect on C6 cells (IC50: 49 micromol/l). The derivatives of tamoxifen, nafoxidine and clomiphene, caused reduction of living cell number in a dose-dependent manner. These two drugs showed differences in their potency following 24-hour incubation in a humidified atmosphere with 37 degrees C and 5% CO2. Obtained from a tetrazolium-formazan growth rate assay, IC50 of nafoxidine for C6 cells was calculated as 44 micromol/l and for the human cells as 16.5 micromol/l. The calculated IC50 dose of clomiphene for C6 is 16 micromol/l and for the human cells 13 micromol/l. Compared to the other drugs we used, it is clear that clomiphene is the most efficient inhibitor of C6 and the human glioma cells. These preliminary results suggest that nafoxidine and clomiphene possess antiproliferative effect on two different sources of glioma cells and therefore, instead of tamoxifen, multiple activities of these drugs may enable their use in combination therapy of glioblastoma malignancies.
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PMID:Comparison of the antiproliferative properties of antiestrogenic drugs (nafoxidine and clomiphene) on glioma cells in vitro. 1528 32

Tamoxifen, a member of the selective estrogen receptor modulator (SERM) family, is widely used in the treatment of estrogen receptor (ER)-expressing breast cancer. It has previously been shown that high-dose tamoxifen has cytotoxic activity against glioma cells, but whether this effect is drug specific or represents a general property of SERMs is unknown. In this study, we demonstrate that tamoxifen and CC-8490, a novel benzopyranone with SERM activity, induce glioma cell apoptosis in a dose- and time-dependent manner. Moreover, administration of tamoxifen and CC-8490 suppresses tumor growth in vivo and extends animal survival in glioma xenograft models. None of the eight glioma cell lines examined express either ER-alpha or -beta, suggesting the mechanism for tamoxifen- and CC-8490-induced glioma cell apoptosis is independent of the ER signaling pathway. Complementary DNA microarray expression profiling allowed us to identify a subset of genes specifically regulated by tamoxifen and CC-8490, and not by other apoptotic stimuli, including nuclear factor (NF)-kappaB with its target genes IEX-3, SOD2, IL6, and IL8. We demonstrate that suppression of NF-kappaB activation markedly enhances SERM-induced apoptosis, suggesting a role for NF-kappaB in protecting glioma cells from SERM-induced cytotoxicity. These findings demonstrate for the first time that a SERM other than tamoxifen can induce glioma cell apoptosis in vitro and in vivo and that the clinical efficacy of SERMs for the treatment of malignant gliomas could potentially be enhanced by simultaneous inhibition of the NF-kappaB pathway.
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PMID:Agents with selective estrogen receptor (ER) modulator activity induce apoptosis in vitro and in vivo in ER-negative glioma cells. 1560 81

Tamoxifen causes apoptosis of malignant glial cells at a concentration that does not kill normal astrocytes. C6 glioma cells were stably transfected with a vector expressing Bcl-2 under the control of metallothionin promoter. Low leaky Bcl-2 expression offered complete protection against tamoxifen-induced apoptosis. High Bcl-2 levels, on the other hand, accelerated the apoptosis, with Bcl-2-overexpressing clones dying within 48 h of tamoxifen treatment as compared to 6 days for parental C6 cells. Overexpressed Bcl-2 is localized primarily in mitochondria and to a much lower extent in endoplasmic reticulum (ER). Only a minor fraction of the overexpressed Bcl-2 gets phosphorylated in tamoxifen-treated cells and the phosphorylation does not affect its binding to Bax. Tamoxifen treatment of Bcl-2-overexpressing clones was found to result in activation of c-Jun N-terminal kinase (JNK) and p38 kinase. Inhibition of JNK but not p38 kinase completely abrogated the accelerated apoptosis. Constitutively expressed endogenous c-Jun was found to be phosphorylated, resulting in increased activator protein 1 (AP-1) DNA-binding activity. Expression of Fas ligand (FasL), an AP-1 transcriptional target, increased during accelerated cell death. This presumably brought about activation of caspase 8, as inhibition of caspase 8 blocked the apoptosis. The JNK/c-Jun/AP-1/FasL pathway could be considered as a potential target for the therapy of gliomas.
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PMID:Activated JNK brings about accelerated apoptosis of Bcl-2-overexpressing C6 glioma cells on treatment with tamoxifen. 1560 91

Irradiation-induced brain injury, leading to cognitive impairment several months to years after whole brain irradiation (WBI) therapy, is a common health problem in patients with primary or metastatic brain tumor and greatly impairs quality of life for tumor survivors. Recently, it has been demonstrated that a rapid and sustained increase in activated microglia following WBI led to a chronic inflammatory response and a corresponding decrease in hippocampal neurogenesis. Tamoxifen, serving as a radiosensitizer and a useful agent in combination therapy of glioma, has been found to exert anti-inflammatory response both in cultured microglial cells and in a spinal cord injury model. In the present study, we investigated whether tamoxifen alleviated inflammatory damage seen in the irradiated microglia in vitro and in the irradiated brain. Irradiating BV-2 cells (a murine microglial cell line) with various radiation doses (2-10 Gy) led to the increase in IL-1 beta and TNF-alpha expression determined by ELISA, and the conditioned culture medium of irradiated microglia with 10 Gy radiation dose initiated astroglial activation and decreased the number of neuronal cells in vitro. Incubation BV-2 cells with tamoxifen (1 microM) for 45 min significantly inhibited the radiation-induced microglial inflammatory response. In the irradiated brain, WBI induced the breakdown of the blood-brain barrier permeability at day 1 post irradiation and tissue edema formation at day 3 post-radiation. Furthermore, WBI led to microglial activation and reactive astrogliosis in the cerebral cortex and neuronal apoptosis in the CA1 hippocampus at day 3 post-radiation. Tamoxifen administration (i.p., 5 mg/kg) immediately post radiation reduced the irradiation-induced brain damage after WBI. Taken together, these data support that tamoxifen can decrease the irradiation-induced brain damage via attenuating the microglial inflammatory response.
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PMID:Tamoxifen alleviates irradiation-induced brain injury by attenuating microglial inflammatory response in vitro and in vivo. 2004 83

The study aimed to examine the tolerability of the combination of radiotherapy and tamoxifen and the effect on median and event free survival as well as collecting data on the use of steroids in this population. 31 patients with diffuse intrinsic pontine glioma, diagnosed on clinical and radiological criteria, were treated with high-dose oral tamoxifen (120 mg/m(2)/day) given concomitantly with standard dose radiotherapy (54 Gy in 1.8 Gy fractions over 6 weeks). Results Tamoxifen was well tolerated with no grade 3 or 4 CTC toxicity reported. At 1 year, the progression free and event free survival were 3.2% (95% CI: 0.2-14.1%), and at 6 months 19.4% (CI: 7.9% to 34.6%). The overall survival at 1 year was 16.1% (CI: 5.9-30.9%) with median survival 6.32 months. In this study, in which tamoxifen was used in conjunction with radiotherapy, progression free survival was shown to be less good when compared with historical data HR = 3.1 (CI: 1.7-5.7). There was no significant reduction in overall survival. The addition of high-dose tamoxifen, although well tolerated, confers no clinical benefit to patients treated with diffuse intrinsic pontine glioma treated with standard radiotherapy.
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PMID:The addition of high-dose tamoxifen to standard radiotherapy does not improve the survival of patients with diffuse intrinsic pontine glioma. 2023 35


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