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

Survivin is an inhibitor of apoptosis protein that blocks apoptosis by binding to caspases-3 and -7. It is highly expressed in less-differentiated embryonic cells and rapidly dividing tumors, but not in terminally differentiated adult tissues. Elevated survivin levels are found in malignant systemic tumors, and are associated with chemo-resistance, radiation resistance, and poor prognosis. However, expression of survivin in primary nervous system tumors has not been previously characterized. Immunohistochemistry using anti-human survivin antibody (SURV11-A) was performed on formalin-fixed, paraffin-embedded archival tissue from 112 primary central nervous system tumors. Survivin immunoreactivity was seen in most diffuse astrocytomas [WHO II (2/4), III (3/3), IV (9/10), giant-cell glioblastoma (1), and gliosarcoma (1)]. The intensity and degree of survivin expression showed trends with tumor grade, with glioblastomas having the highest positivity. Pilocytic astrocytomas (5) and pleomorphic xanthoastrocytoma (1) were positive to a lesser degree. In oligodendrogliomas (6) and mixed oligo-astrocytomas [grade II (5), II-III (3), and III (7)], oligodendroglial elements appear to be negative compared to positive mini-gemistocytic oligodendrocytes. Ependymomas [grade II (6) and grade III (1)] were positive. Medulloblastomas (5) and retinoblastoma (1/4) showed focal positivity. All meningiomas [grade I (12), II (9), III (4), and grade I (3) and II (5) with frank brain invasion] were intensely positive. All schwannomas (11) and neurofibromas (6) were intensely positive. Thus, survivin is expressed in the majority of the primary nervous system tumors, particularly in glioblastomas, meningiomas, schwannomas and neurofibromas. Overexpression of survivin in meningiomas and benign peripheral nerve sheath tumors contrasts with previous reports relating it to rapid division and poor prognosis.
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PMID:Expression of survivin, an inhibitor of apoptosis protein, in tumors of the nervous system. 1207 Jun 71

Glioblastoma multiforme (GBM) is a highly malignant brain tumor that is resistant to conventional radiotherapy and chemotherapy. The median survival time of patients with GBM has remained less than 2 years despite concerted efforts to improve therapy. As a new approach to treat GBM we generated retroviral particles encoding mutant survivin for transduction of glioma cells. We demonstrate here that retroviral overexpression of a nonphosphorylatable Thr-34 --> Ala mutant of survivin (survivinT34A), in the glioma cell lines U373 and H4 resulted in a marked increase in the percentage of cells bearing multiple nuclei, which was accompanied by significantly decreased cell proliferation, and in greater numbers of cells with hypodiploid DNA content. Administration of the broad caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethyl-ketone did not reduce the cell death rate. Yet increased nuclear translocation of apoptosis-inducing factor (AIF) was observed in cells transduced with survivinT34A, indicating caspase-independent cell death. Transduction of retroviral vectors encoding wild-type survivin also led to the appearance of multinuclear cells. In contrast to mutant survivin, overexpressed wild-type survivin did not increase the cell death rate and no enhanced nuclear AIF translocation was observed. We suggest that retroviral vectors delivering mutant survivinT34A might be employed for the treatment of glioblastoma.
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PMID:Inhibition of malignant glioma cell growth by a survivin mutant retrovirus. 1576 Dec 61

Survivin is a member of a novel protein family of inhibitors of apoptosis, and also plays a role as a potent regulator of mitosis. In semiquantitative Western blot analysis of glioblastomas, survivin expression was shown to be a prognostically significant factor. In the present study we investigated the immunohistochemical expression of survivin and its prognostic impact in a large glioblastoma series comprising 104 consecutive adult patients undergoing a first operation for glioblastoma. We analyzed survivin, Ki-67, and topoisomerase-II-alpha expression in paraffin-embedded tissue, and correlated patient age, Karnofsky performance score, vascular pattern and survivin-, Ki-67-, topoisomerase-II-alpha-, and apoptotic indices with patient outcome using univariate and multivariate survival analysis. Survivin was expressed in all glioblastoma samples, and was prominent in a fraction of nuclei of tumor cells and vascular cells. Further, survivin labeled spindle- and chromosomal material of mitotic figures. Faint cytoplasmic expression was also seen. The survivin index showed significant correlation with Ki-67 and Topo-II-alpha indices. On average, 58.85% of Ki-67 and 91.08% of survivin-expressing nuclei co-expressed Ki-67 and survivin. The survivin index did not correlate significantly with overall survival, whereas patient age, Karnofsky performance score, vascular pattern, and Ki-67 and topoisomerase-II-alpha indices were associated with patient outcome. In summary, in glioblastoma, survivin is expressed predominantly in proliferating tumor cell nuclei. In contrast to Ki-67 and topoisomerase-II-alpha, survivin expression does not influence patient outcome. So, in contrast to Ki-67, survivin does not seem to be useful as prognostic factor in the clinical setting.
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PMID:No prognostic impact of survivin expression in glioblastoma. 1584 6

Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also interacts and forms complexes with proteins important in extracellular matrix organization and cellular adhesion. We have identified the novel finding that treatment of glioblastoma cells with transglutaminase 2 inhibitors promotes cell death and enhances sensitivity to chemotherapy. Treatment with either the competitive transglutaminase 2 inhibitor, monodansylcadaverine, or with highly specific small-molecule transglutaminase 2 inhibitors, KCA075 or KCC009, results in induction of apoptosis in glioblastoma cells. Treatment with these transglutaminase 2 inhibitors resulted in markedly decreased levels of the prosurvival protein, phosphorylated Akt, and its downstream targets. These changes promote a proapoptotic profile with altered levels of multiple intracellular proteins that determine cell survival. These changes include decreased levels of the antiapoptotic proteins, survivin, phosphorylated Bad, and phosphorylated glycogen synthetase kinase 3beta (GSK-3beta), and increased levels of the proapoptotic BH3-only protein, Bim. In vivo studies with s.c. murine DBT glioblastoma tumors treated with transglutaminase 2 inhibitors combined with the chemotherapeutic agent, N-N'-bis (2-chloroethyl)-N-nitrosourea (BCNU), decreased tumor size based on weight by 50% compared with those treated with BCNU alone. Groups treated with transglutaminase 2 inhibitors showed an increased incidence of apoptosis determined with deoxynucleotidyl transferase-mediated biotin nick-end labeling staining. These studies identify inhibition of transglutaminase 2 as a potential target to enhance cell death and chemosensitivity in glioblastomas.
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PMID:Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas. 1617 20

Genomic instability and apoptosis evasion are hallmarks of cancer, but the molecular mechanisms governing these processes remain elusive. Here, we found that survivin, a member of the apoptosis-inhibiting gene family, and aurora B kinase, a chromosomal passenger protein, were co-overexpressed in the various glioblastoma cell lines and tumors. Notably, exogenous introduction of the aurora B in human BJ cells was shown to decrease cell growth and increase the senescence-associated beta-galactosidase activity by activation of p53 tumor suppressor. However, aurora B overexpression failed to inhibit cell proliferation in BJ and U87MG cells transduced with dominant-negative p53 as well as in p53(-/-) mouse astrocytes. Aurora B was shown to increase centrosome amplification in the p53(-/-) astrocytes. Survivin was shown to induce anchorage-independent growth and inhibit anti-proliferation and drug-sensitive apoptosis caused by aurora B. Overexpression of both survivin and aurora B further accelerated the proliferation of BJ cells. Taken together, the present study indicates that survivin should accelerate tumorigenesis by inhibiting the anti-proliferative effect of p53 tumor suppressor that is activated by aurora B in normal and glioblastoma cells containing intact p53.
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PMID:Survivin inhibits anti-growth effect of p53 activated by aurora B. 1617 86

Lithium is the most widely prescribed mood stabilizer, but the precise molecular mechanisms underlying its therapeutic function are not yet fully elucidated. Recent preclinical and clinical evidence indicates its neuroprotective and neurotrophic effects. As a tight coupling of function and metabolism in the central nervous system between glial cells and neurons has recently been detected, lithium's effect on glial cells may participate also in the total beneficial effects of this drug. The aim of the present study was to analyze molecular mechanisms induced in human glioblastoma A1235 cells by the treatment with lithium, especially its influence on the expression of apoptosis-related genes. Lower levels of lithium (0.5 mmol/L and 2 mmol/L) did not cause any cytotoxicity or changes in the cell cycle phase distribution following 72 h incubation. However, a higher dose (20 mmol/L) was cytostatic for glioblastoma cells, and caused accumulation of cells in G(2)/M phase of the cell cycle. The treatment with lithium did not alter the levels of Bcl-2 or procaspase-3 and did not cleave PARP, but increased the levels of p21(WAF/Cip1) and survivin. Thus, increased expression of p21(WAF/Cip1) (a protein with antiapoptotic function), and survivin (a protein that supports the growth of cells by suppression of apoptosis and promotion of cell proliferation) may be the early events in the long-term cell response to lithium that are involved in the beneficial effects of this drug.
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PMID:Lithium increases expression of p21(WAF/Cip1) and survivin in human glioblastoma cells. 1710 31

Hypoxia is a characteristic feature of advanced solid tumors and may worsen prognosis. The development of tumor-targeted and hypoxia-inducible gene therapy vectors holds promise to selectively deliver and express suicidal or cytotoxic genes in hypoxic regions of tumors. In this regard, the promoter of the survivin gene, which encodes an anti-apoptotic protein that is strongly expressed in tumor tissue, has received attention because of its supposed inducibility by hypoxia. However, in our present study we demonstrate that treatment of various tumor cell lines with chronic hypoxia or with the hypoxia-mimetic CoCl(2) does not result in increased expression of survivin, but rather strongly suppresses this gene's activity. In contrast, expression of glucose-regulated protein 78 (GRP78/Bip) is substantially elevated under chronic hypoxia in vitro and in hypoxic areas of tumor tissue in vivo. Although tumor cells in general exhibit increased chemoresistance under hypoxic conditions, we found that hypoxic glioblastoma cells are more sensitive to killing by the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib, and this effect is reflected by further decreased expression of survivin. Intriguingly, 2,5-dimethyl-celecoxib (DMC), a close structural analog of celecoxib that lacks the ability to inhibit COX-2, is able to potently mimic the anti-tumor effects of its parent compound, indicating that inhibition of COX-2 is not involved in these processes. Taken together, our results caution against the use of survivin-based promoters to target hypoxic areas of tumors, but favor constructs that include the strongly hypoxia-inducible GRP78 promoter. In addition, our data introduce celecoxib as a drug with increased cytotoxicity against hypoxic tumor cells.
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PMID:Reduced survivin expression and tumor cell survival during chronic hypoxia and further cytotoxic enhancement by the cyclooxygenase-2 inhibitor celecoxib. 1744 Aug 35

Glioblastoma is the most common brain tumor that causes significant mortality annually. Limitations of the current therapeutic regimens warrant development of new techniques and treatment strategies in orthotopic animal model for better management of this devastating brain cancer. There are only a few experimental orthotopic models of glioblastoma for pre-clinical testing. In the present investigation, we successfully implanted rat C6 cells via intracranial stereotaxic cannulation in adult Sprague-Dawley rats for development and histoimmunopathological characterization of an advanced orthotopic glioblastoma allograft model, which could be useful for investigating the course of glioblastoma development as well as for testing efficacy of new therapeutic agents. The orthotopic glioblastoma allograft was generated by intracerebral injection of rat C6 cells through a guide-cannula system and after 21 post-inoculation days the brain tumor was characterized by histoimmunopathological experiments. Histological staining and immunofluorescent labelings for TERT, VEGF, Bcl-2, survivin, XIAP, and GFAP revealed the distinct characteristics of glioblastoma in C6 allograft, which could be useful as a target for treatment with emerging new therapeutic agents. Our investigation indicated the successful development of intracranial cannulated orthotopic glioblastoma allograft in adult Sprague-Dawley rats, making it as a useful animal model of glioblastoma for pre-clinical evaluation of various therapeutic strategies for the management of glioblastoma.
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PMID:Intracranial stereotaxic cannulation for development of orthotopic glioblastoma allograft in Sprague-Dawley rats and histoimmunopathological characterization of the brain tumor. 1770 49

In order to enhance the cytotoxicity of radiation, camptothecin (CPT), an inhibitor of DNA topoisomerase I, was added to the cultured glioma cell lines before irradiation (IR). Radiation responses of five glioblastoma cell lines (U87-MG, U373-MG, GHE, GaMG and SNB-19) treated with CPT were analyzed in terms of cell and colony counts, cell cycle progression, expression of histone gamma H2AX, DNA repair protein Rad50, survivin, cleaved caspase 3, p53 and of topoisomerase I. CPT enhanced the radiotoxicity in U87-MG and SNB-19 cell lines if cell and colony counts were used as the end-points. In contrast, pre-treatment with CPT of U373-MG, GHE and GaMG cell lines did not enhance cytotoxicity of IR in terms of cell and colony counts but accelerated DNA damage repair assessed by Rad50 foci. CPT treated glioma cells revealed at least two subpopulations with respect to the expression of histone gamma H2AX, a marker of DNA double-strand breaks. The cell lines tested also differed in the expression of survivin, cleaved caspase 3, p53 and of topoisomerase I. The failure of CPT to enhance the radiotoxicity of glioma U373-MG, GHE and GaMG cell lines in terms of cell and colony counts was found to correlate with accelerated DNA damage repair, and with low expression of topoisomerase I, a target of CPT.
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PMID:Differential response of human glioblastoma cell lines to combined camptothecin and ionizing radiation treatment. 1861 57

Glioblastoma is the most malignant and prevalent brain tumor in humans. It is composed of heterogenic abnormal astroglial cells that avoid differentiation, maintain proliferation, and hardly commit apoptosis. N-(4-Hydroxyphenyl)retinamide (4-HPR) induced astrocytic differentiation and increased sensitivity to interferon-gamma (IFN-gamma) for apoptosis in human glioblastoma A172, LN18, and SNB19 cells. Combination of 4-HPR and IFN-gamma significantly inhibited human telomerase reverse transcriptase (hTERT), cyclin dependent kinase 2 (CDK2), and survivin to up-regulate caspase-8, caspase-9, and caspase-3 for increasing apoptosis in all glioblastoma cell lines. Hence, combination of 4-HPR and IFN-gamma should be considered for controlling growth of different human glioblastoma cells.
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PMID:N-(4-Hydroxyphenyl)retinamide induced differentiation with repression of telomerase and cell cycle to increase interferon-gamma sensitivity for apoptosis in human glioblastoma cells. 1816 43


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