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)

Antineoplastic intercalating agents such as 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) stabilize a cleavable complex between topoisomerase II and DNA. The production of protein-associated DNA cleavage in whole cells exposed to m-AMSA is thought to represent the cellular correlate of this topoisomerase II-mediated reaction. Protein-associated DNA cleavage can be quantified in mammalian cells by using alkaline elution technology. In an attempt to understand the impact of phenotypic and biochemical cellular characteristics on protein-associated DNA cleavage, we quantified m-AMSA-induced DNA cleavage in quiescent or proliferative normal human fibroblasts (cell strain 1508) and human glioblastoma cells (line T98G) as well as in asynchronously proliferating HeLa cells. The magnitude of DNA cleavage in quiescent fibroblasts and quiescent glioblastoma cells was identical and low relative to that observed in the HeLa cells. The magnitude of DNA cleavage was enhanced in both cell types following proliferation. This enhancement was greater in the glioblastoma cells than in the fibroblasts. These results were not due to alterations in cellular m-AMSA uptake. Chromatin was more elongated (open) in the quiescent glioblastoma cells than in the quiescent fibroblasts (as visualized by using the premature chromosome condensation assay), suggesting chromatin accessibility to drug per se may not be a critical determinant of the magnitude of m-AMSA-induced DNA cleavage. The onset of the enhanced m-AMSA-induced DNA cleavability that accompanied proliferation closely followed the formation of regions of localized chromatin decondensation, a late G1 event, and coincided with the onset of enhanced thymidine uptake, a marker for the onset of S phase. m-AMSA-induced cytotoxicity was also enhanced in proliferating compared with quiescent cells. The major finding of this study is that the cellular target for m-AMSA, putatively topoisomerase II, is more susceptible to drug action in proliferating cells than in quiescent cells. Effects of chromatin conformation or cellular phenotype upon topoisomerase II-mediated events such as m-AMSA-induced DNA cleavage are less certain.
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PMID:Effect of cell proliferation and chromatin conformation on intercalator-induced, protein-associated DNA cleavage in human brain tumor cells and human fibroblasts. 302 17

The inhibition by IFN-beta of acquired resistance to the epipodophillotoxin etoposide was studied using a human glioblastoma cell line, T98G. T98G cells were exposed to either etoposide alone or both etoposide and IFN-beta, and after subculture, the same two series of drug exposure were repeated. Degree of level of resistance was tested by the response of the cells to etoposide and changes in their DNA histograms. Furthermore, topoisomerase II in each set of cells was subjected to fluorescence staining with monoclonal anti-topoisomerase II antibody, and the amount of fluorescence was measured by flow cytometry. Secondary etoposide exposure showed less cytotoxicity when the first exposure was to etoposide alone. In contrast, the cytotoxicity was almost the same as that after the first exposure when IFN-beta was added. Resistance to etoposide may result from qualitative or quantitative alterations in the target enzyme, topoisomerase II. The present results show that resistant cells have less topoisomerase II than sensitive cells, suggesting that IFN-beta inhibits the acquisition of resistance to etoposide by suppressing the alteration in topoisomerase II. The inhibition of acquired resistance to etoposide by IFN-beta suggests that continuous and repeated chemotherapy for glioblastoma and other malignant tumors may be clinically advantageous.
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PMID:IFN-beta inhibition of etoposide resistance acquisition in vitro: studies using a human glioblastoma cell line. 776 95

We have evaluated the DNA breaks occurring after action of three topoisomerase II-interfering drugs (doxorubicin, etoposide and amsacrine) on a line of rat glioblastoma cells in culture and its doxorubicin-resistant variant. DNA breaks were quantified by alkaline unwinding in the presence of a dye exhibiting a quenching of fluorescence with single stranded DNA. The antiproliferative activity of the three drugs was compared to their ability to damage DNA. We have shown that at low exposure doses (up to the IC50 of the drugs), the same low level of DNA damage determined the same inhibition of cell growth in sensitive and resistant cells, but that at higher exposure doses the resistant cells developed special mechanisms allowing them to tolerate more DNA breaks than sensitive cells without lethal effects. The origin of this tolerance of resistant cells to DNA breaks might be due to special mechanisms of protection of genomic sites hypersensitive to topoisomerase II-mediated drug action, to alterations of topoisomerase II or to alterations of the molecular events leading to cell death after occurrence of DNA breaks.
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PMID:Relationships between DNA damage and growth inhibition induced by topoisomerase II-interfering drugs in doxorubicin-sensitive and -resistant rat glioblastoma cells. 816 63

Using the technique of alkaline filter elution, we have evaluated the DNA damage induced by doxorubicin and etoposide in a rat glioblastoma cell line, C6, and its doxorubicin-selected resistant variant, C6 0.5. DNA damage paralleled drug-induced cytotoxicity, but it appeared that the same DNA damage generated much less cytotoxicity in resistant cells than in sensitive ones, resistant cells being able to tolerate more DNA damage than sensitive cells. We have then quantified the doxorubicin- and etoposide-induced complexes between topoisomerase II (topoII) DNA with the technique of SDS/KCl precipitation. Etoposide produced a concentration-dependent increase in topoII-DNA complexes, which was higher in resistant cells at equitoxicity, just as was DNA damage. In contrast, doxorubicin-induced topoII-DNA complexes, which were much less abundant than those induced by etoposide, were not differently produced in sensitive and resistant cells. This indicates that the DNA damage occurring in resistant cells at high doxorubicin concentrations might originate from source other than topoII-DNA complex formation. When verapamil was added during drug exposure, it restored doxorubicin intracellular accumulation to the level reached in sensitive cells, partially reversed both doxorubicin and etoposide resistance, increased the formation of etoposide-induced topoII-DNA complexes, but not those induced by doxorubicin. Immunoblot analysis of topoII as well as the measure of its catalytic activity in nuclear extracts revealed a quantitative defect of this enzyme in the resistant line. When inhibiting this activity by doxorubicin and etoposide, we observed that the concentrations of etoposide required for a given inhibition of kinetoplast DNA decatenation are much higher that those of doxorubicin. The topoII extracted from both cell lines is, therefore, much more sensitive to doxorubicin than to etoposide, but no difference in drug sensitivity was evident between sensitive and resistant cells, indicating that no qualitative alteration in topoII catalytic activity was likely to occur.
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PMID:Differential stabilization of topoisomerase-II-DNA cleavable complexes by doxorubicin and etoposide in doxorubicin-resistant rat glioblastoma cells. 915 58

Protoberberines are a new class of organic cations that are dual poisons of topoisomerases I and II. Certain protoberberines exhibit greater in vitro cytotoxicity against cell lines derived from solid tumors than from leukemias. Using a group of seventeen different protoberberine analogs, the structural basis for selective cytotoxicity toward sensitive SF-268 glioblastoma cells as compared with resistant RPMI 8402 lymphoblast cells was explored. The selective cytotoxicity is associated with the presence of an imminium ion and other structural features of protoberberines, and is not shared by drugs such as camptothecin, doxorubicin, vinblastine, and etoposide, which are either equally or more cytotoxic against RPMI 8402 cells than SF-268 cells. The selective cytotoxicity of protoberberines against SF-268 over RPMI 8402 cells is not due to differences in topoisomerase levels or known drug efflux systems such as multidrug resistance (MDR1) and multidrug-resistance protein (MRP). Comparative in vitro studies of the accumulation of coralyne, a fluorescent protoberberine, into sensitive and resistant cells demonstrated a correlation between drug accumulation and selective cytotoxicity. Inhibitors of coralyne uptake included several protoberberine-related compounds. Of these, palmatine, a minimally cytotoxic protoberberine, both inhibited coralyne accumulation and reduced cytotoxicity against SF-268 cells, but not against RPMI 8402 cells. Despite the structural resemblance of protoberberines to catecholamines, our experiments using inhibitors and cells expressing biogenic amine uptake systems have ruled out the involvement of biogenic amine uptake1, uptake2, and vesicular monoamine transport systems. Uptake systems remaining as candidates, supported by preliminary data, include transport via vesicles derived from specialized membrane invaginations and selected carrier-mediated organic amine transport systems.
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PMID:Selective cytotoxicity of topoisomerase-directed protoberberines against glioblastoma cells. 980 26

Cells lacking an intact ATM gene are hypersensitive to ionizing radiation and show multiple defects in the cell cycle-coupled checkpoints. DNA damage usually triggers cell cycle arrest through, among other things, the activation of p53. Another DNA-damage responsive factor is NF-kappaB. It is activated by various stress situations, including oxidative stress, and by DNA-damaging compounds such as topoisomerase poisons. We found that cells from Ataxia Telangiectasia patients exhibit a defect in NF-kappaB activation in response to treatment with camptothecin, a topoisomerase I poison. In AT cells, this activation is shortened or suppressed, compared to that observed in normal cells. Ectopic expression of the ATM protein in AT cells increases the activation of NF-kappaB in response to camptothecin. MO59J glioblastoma cells that do not express the DNA-PK catalytic subunit respond normally to camptothecin. These results support the hypothesis that NF-kappaB is a DNA damage-responsive transcription factor and that its activation pathway by DNA damage shares some components with the one leading to p53 activation.
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PMID:The ATM protein is required for sustained activation of NF-kappaB following DNA damage. 1032 72

KILLER/DR5 is a death-domain-containing proapoptotic receptor that binds to the cytotoxic ligand TRAIL. It was originally reported that induction of KILLER/DR5 mRNA following DNA damage was p53-dependent, but some drugs that induce apoptosis can upregulate KILLER/DR5 mRNA expression in cell lines with mutated p53. We further extend those findings by classifying the capability of various apoptosis-inducing drugs to increase the expression of KILLER/DR5 mRNA in a p53-independent manner. beta-Lapachone, a topoisomerase inhibitor, increased KILLER/DR5 mRNA in colon cancer cell lines with wild-type p53 but not with mutant p53. In contrast, betulinic acid, a novel chemotherapeutic compound, induced apoptosis and KILLER/DR5 mRNA in melanoma and glioblastoma cells through a p53-independent mechanism. The synthetic glucocorticoid dexamethasone elevated KILLER/DR5 mRNA in glioblastoma, ovarian cancer, and colon cancer cell lines with mutant p53 undergoing apoptosis, and this induction was inhibited by the transcriptional inhibitor actinomycin D. Although another glucocorticoid, prednisolone, also induced apoptosis, it did not increase KILLER/DR5 mRNA. Finally, the cytokine interferon-gamma (IFN-gamma) induced apoptosis and KILLER/DR5 in cell lines with mutant p53, and the induction of KILLER/DR5 mRNA by IFN-gamma was delayed in cells lacking wild-type STAT1, a transcription factor implicated in IFN-gamma signaling. Similarly, the induction of KILLER/DR5 mRNA by the cytokine TNF-alpha was also delayed in cell lines with mutated STAT1. These findings suggest that KILLER/DR5 may play a role in p53-independent apoptosis induced by specific drugs and warrants further investigation as a novel target for chemotherapy of tumors lacking wild-type p53.
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PMID:p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. 1113 40

Because the activities of HER family members are elevated and/or aberrant in a variety of human neoplasms, these cell surface receptors are receiving increasing attention as potential therapeutic targets. In the present study, we examined the effect of combining the HER family tyrosine kinase inhibitor CI1033 (PD 183805) with the topoisomerase (topo) I poison 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, in a number of different cell lines. Colony-forming assays revealed that the antiproliferative effects of simultaneous treatment with CI1033 and SN-38 were synergistic in T98G glioblastoma cells and HCT8 colorectal carcinoma cells, whereas sequential treatments were additive at best. In additional studies examining the mechanistic basis for these findings in T98G cells, immunoblotting revealed that the inhibitory effects of CI1033 on epidermal growth factor receptor autophosphorylation were unaffected by SN-38. Likewise, CI1033 had no effect on topo I polypeptide levels, localization, or activity. Nonetheless, CI1033 markedly enhanced the number of covalent topo I-DNA complexes stabilized by SN-38 or the related agent topotecan (TPT). Analysis of intracellular SN-38 levels by high-performance liquid chromatography and intracellular TPT levels by flow microfluorometry revealed that CI1033 increased the steady-state accumulation of SN-38 and TPT by 9.4 +/- 1.9- and 1.8 +/- 0.2-fold, respectively. Further evaluation revealed that the initial rate of TPT uptake was unaffected by CI1033, whereas the rate of efflux was markedly diminished. Additional studies demonstrated that T98G and HCT8 cells express the breast cancer resistance protein (BCRP), a recently cloned ATP binding cassette transporter. Moreover, CI1033 enhanced the uptake and cytotoxicity of SN-38 and TPT in cells transfected with BCRP but not empty vector. Conversely, CI1033 accumulation was diminished in cells expressing BCRP, suggesting that CI1033 is a substrate for this efflux pump. These results indicate that CI1033 can modulate the accumulation and subsequent cytotoxicity of two widely used topo I poisons in cells that have no history of previous exposure to these agents.
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PMID:The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. 1121 77

Staurosporine, a protein kinase and etoposide, a topoisomerase II inhibitor, are known to enhance apoptosis. The differential effects of these agents on T98G glioblastoma and SK-N-SH neuroblastoma, cell lines both derived from human tumors, have not been determined. We assessed cellular viability, DNA fragmentation and laddering, chromatin condensation, and Poly(ADP-ribose) polymerase (PARP) cleavage induced by these agents at a series of concentrations and times. In addition, to gain an understanding of the mechanism by which these agents work, we measured Protein Kinase C (PKC) activity. Staurosporine induced significant alterations in all apoptotic parameters tested in both cell lines. Etoposide induced apoptotic alterations similar to those caused by staurosporine in neuroblastoma but produced no detectable apoptotic changes in glioblastoma cells. Etoposide induced membrane but not cytosolic PKC activity in neuroblastoma but had no effect on PKC activity in glioblastoma. Our results show that the induction of apoptosis is cell type dependent. PKC activity appears to be crucial in the initiation of apoptosis.
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PMID:Differential responses of human neuroblastoma and glioblastoma to apoptosis. 1145 93

Radiotherapy is the standard treatment for glioblastoma. Here, we assessed the radiosensitivity of 12 human malignant glioma cell lines in vitro and correlated these data with irradiation-induced cell cycle changes, chemosensitivity profiles and BCL-2 family protein expression. Irradiation at 3 Gy failed to cause major cell cycle perturbations. Radioresistance was associated with collateral sensitivity to the topoisomerase II inhibitors, teniposide and doxorubicin. High levels of BCL-XL and low levels of BAX were independently linked to radioresistance. Ectopic expression of a BAX transgene induced radiosensitization in the LN-18 cell line. Thus, BCL-2 family protein expression modulates radiosensitivity in human glioma cells and targeted alterations in BCL-2 family protein expression are a promising strategy to improve the therapeutic efficacy of radiotherapy for gliomas.
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PMID:BCL-2 family proteins modulate radiosensitivity in human malignant glioma cells. 1194 26


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