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 goal of this study was to determine whether ultrasound (US) exposure combined with microbubble destruction could be used to enhance non-viral gene delivery in rat C6 glioma cells. Microbubbles were prepared and gently mixed with plasmid DNA. The mixture of the DNA and microbubbles was administered to cultured C6 cells under different US/microbubble conditions. Transfection efficiency and cell viability were assessed by FACS analysis, confocal laser scanning microscopy, and Trypan blue staining. The results demonstrate that microbubble with US exposure could significantly enhance the reporter gene expression as compared with other groups. No statistical significant difference was observed in the glioma cell viability between different groups. Our in vitro findings suggest that US-mediated microbubble destruction has the potential to promote safe and efficient gene transfer into C6 cells. This non-invasive gene transfer method may be useful for safe clinical gene therapy of brain cancer without a viral vector system.
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PMID:Ultrasound-mediated microbubble destruction facilitates gene transfection in rat C6 glioma cells. 1861 90

D-amino acid oxidase (DAAO) can catalyze the dehydrogenation of D-amino acids, such as D-alanine, to the corresponding amino acids and is then reoxidized by molecular oxygen to yield hydrogen peroxide, a reactive oxygen species, which reacts with DNA, lipids and protein, inducing cell death. This study investigated whether rat glioma 9L cells infected with the recombinant retrovirus containing the DAAO cDNA fragment can be induced in order to undergo cytotoxic oxidative stress by D-alanine. The recombinant retroviral vector, plzrus-DAAO-FLAG-GFP (pl-Dfg), was constructed and used to transfect packaged phoenix cells. The supernatant containing recombinant retroviral particles from the transfected phoenix cells was harvested and utilized to infect target 9L cells. The cytotoxic oxidative stress of infected 9L cells was induced by the DAAO substrate, D-alanine. The plasmid pl-Dfg was successfully constructed. The high titer retroviral supernatant was obtained from the transfected phoenix cells. Infected 9L cells were less viable after exposure to D-alanine compared to the control group. Anti-apoptotic proteins significantly inhibited cell death. The DAAO/D-alanine system has a potential utility for gene therapy and may be an effective strategy for the treatment of brain cancer and other malignant tumors.
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PMID:Transfection of the DAAO gene and subsequent induction of cytotoxic oxidative stress by D-alanine in 9L cells. 1863 95

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer that is characterized by the paradoxical features of intense apoptosis resistance yet a marked propensity to undergo necrosis. Bcl2L12 (for Bcl2-Like12) is a nuclear and cytoplasmic oncoprotein that is universally overexpressed in primary GBM and functions to block postmitochondrial apoptosis signaling by neutralizing effector caspase-3 and caspase-7 maturation. This postmitochondrial block in apoptosis engenders the alternate cell fate of cellular necrosis, thus providing a molecular explanation for GBM's classical features. Whereas Bcl2L12-mediated neutralization of caspase-7 maturation involves physical interaction, the mechanism governing Bcl2L12-mediated inhibition of caspase-3 activity is not known. The nuclear localization of Bcl2L12 prompted expression profile studies of primary astrocytes engineered to overexpress Bcl2L12. The Bcl2L12 transcriptome revealed a striking induction of the small heat shock protein alpha-basic-crystallin (alphaB-crystallin/HspB5), a link reinforced by robust alphaB-crystallin expression in Bcl2L12-expressing orthotopic glioma and strong coexpression of alphaB-crystallin and Bcl2L12 proteins in human primary GBMs. On the functional level, enforced alphaB-crystallin or Bcl2L12 expression enhances orthotopic tumor growth. Conversely, RNAi-mediated knockdown of alphaB-crystallin in Bcl2L12-expressing astrocytes and glioma cell lines with high endogenous alphaB-crystallin showed enhanced apoptosis, yet decreased necrotic cell death with associated increased caspase-3 but not caspase-7 activation. Mirroring this specific effect on effector caspase-3 activation, alphaB-crystallin selectively binds pro-caspase-3 and its cleavage intermediates in vitro and in vivo. Thus, alphaB-crystallin is a Bcl2L12-induced oncoprotein that enables Bcl2L12 to block the activation of both effector caspases via distinct mechanisms, thereby contributing to GBM pathogenesis and its hallmark biological properties.
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PMID:Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma. 1866 46

The effects of 1-(biphenyl-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6,7-diol (EDL-155) on the growth of glioma was tested in vitro and in vivo. Normal cultured rat astrocytes and C6 rat glioma were used as a differential screen to test the effects of EDL-155. The compound was preferentially cytotoxic for C6 glioma (EC50=1.5 micromol/l) relative to cultured neonatal astrocytes (EC50=27.4 micromol/l). When compared with a standard chemotherapeutic agent, carmustine (1,3-bis[2-chloroethyl]-1-nitrosourea), or temozolomide, EDL-155 was more selective and more potent in our differential tissue culture assay. The effect of EDL-155 was also tested in an animal model in which C6 glioma was transplanted into the brains of Sprague-Dawley rats. EDL-155 was delivered directly onto the tumor by an osmotic minipump directly into the brain or by intraperitoneal injection. Animals treated with EDL-155 had significantly smaller tumors than did control animals treated with carrier solution. We observed anatomical changes in cultured glioma cells treated with EDL-155 that were consistent with selective destruction of mitochondria and the induction of autophagy. These changes were not observed in normal astrocytes cultured from rat pups. The selective killing of glioma in tissue culture and in the rat brain models indicates that EDL-155 has potential therapeutic value in treating this type of brain cancer.
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PMID:Effects, in an in-vivo model system, of 1,2,3,4-tetrahydroisoquinoline on glioma. 1876

Glioblastoma (GBM) is the most common type of primary brain cancer and carries a dismal prognosis primarily due to the emergence of resistance towards extant radiation, conventional and targeted chemotherapies. Although GBM resists therapy-induced apoptosis, tumors show a seemingly paradoxical propensity for florid intratumoral necrogenesis. This necrosis manifests pathologically as microscopic foci or confluent expanses of necrotic tumor. While it is now well recognized that necrosis is an active cell death process and that apoptosis and necrosis death modalities are intertwined on multiple levels, the precise molecular mechanisms and genetic elements underlying these forms of cell death in GBM remain areas of active investigation. In recent oncogenomic studies, we identified a novel GBM oncoprotein, Bcl2-Like 12 (Bcl2L12), which is significantly expressed in the majority of primary GBM tumor specimens and distantly related to canonical Bcl-2 proteins. Due to its distinctive impact on cell death signaling, Bcl2L12 phenocopies pro-necrotic and anti-apoptotic propensities of high grade glioma: Mechanistically, we determined that unlike prototypic Bcl-2 family members, Bcl2L12 does not safeguard mitochondrial membrane integrity, but instead potently inhibits apoptosis at the level of post-mitochondrial effector caspase-3/7 activation. A combination of enforced expression, RNAi-mediated extinction, co-localization and protein interaction studies revealed that Bcl2L12 inhibits caspases 3 and 7 via distinct mechanisms. Direct physical interaction underlies Bcl2L12's inhibition of caspase-7 processing, whereas Bcl2L12-induced transcriptional upregulation of the small heat shock protein alpha B-crystallin is instrumental to neutralization of caspase-3 activation. Mirroring the cellular phenotype elicited by energy depletion, genetic or pharmacologic inhibition of post-mitochondrial apoptosis signaling molecules, Bcl2L12 promotes necrogenesis in glial cells in the context of a proapoptotic stimulus establishing that it represents a novel regulator of the balance between apoptosis and necrosis in GBM.
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PMID:What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator. 1876 59

The cancer relapse and mortality rate suggest that current therapies do not eradicate all malignant cells. Currently, it is accepted that tumorigenesis and organogenesis are similar in many respects, as for example, homeostasis is governed by a distinct sub-population of stem cells in both situations. There is increasing evidence that many types of cancer contain their own stem cells: cancer stem cells (CSC), which are characterized by their self-renewing capacity and differentiation ability. The investigation of solid tumour stem cells has gained momentum particularly in the area of brain tumours. Gliomas are the most common type of primary brain tumours. Nearly two-thirds of gliomas are highly malignant lesions with fast progression and unfortunate prognosis. Despite recent advances, two-year survival for glioblastoma (GBM) with optimal therapy is less than 30%. Even among patients with low-grade gliomas that confer a relatively good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells endowed with features of primitive neural progenitor cells and a tumour-initiating function. In general, this fraction is characterized for forming neurospheres, being endowed with drug resistance properties and often, we can isolate some of them using sorting methods with specific antibodies. The molecular characterization of these stem populations will be critical to developing an effective therapy for these tumours with very dismal prognosis. To achieve this aim, the development of a mouse model which recapitulates the nature of these tumours is essential. This review will focus on glioma stem cell knowledge and discuss future implications in brain cancer therapy and regenerative medicine.
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PMID:Brain tumour stem cells: implications for cancer therapy and regenerative medicine. 1878 2

Malignant brain tumors are among the most lethal cancers, and conventional therapies are largely limited to palliation. Novel therapies targeted against specific molecular pathways may offer superior efficacy and less toxicity than conventional therapies, but initial clinical trials of molecular targeted agents in brain cancer therapy have been frequently disappointing. In brain tumors and other cancers, subpopulations of tumor cells have recently been characterized by their ability to self-renew and initiate tumors. Although these cancer stem cells, or tumor initiating cells, are often only present in small numbers in human tumors, mounting evidence suggests that cancer stem cells contribute to tumor maintenance and therapeutic resistance. Thus, the development of therapies that target cancer stem cell signal transduction and biology may improve brain tumor patient survival. We now demonstrate that populations enriched for cancer stem cells are preferentially sensitive to an inhibitor of Akt, a prominent cell survival and invasion signaling node. Treatment with an Akt inhibitor more potently reduced the numbers of viable brain cancer stem cells relative to matched nonstem cancer cells associated with a preferential induction of apoptosis and a suppression of neurosphere formation. Akt inhibition also reduced the motility and invasiveness of all tumor cells but had a greater impact on cancer stem cell behaviors. Furthermore, inhibition of Akt activity in cancer stem cells increased the survival of immunocompromised mice bearing human glioma xenografts in vivo. Together, these results suggest that Akt inhibitors may function as effective anticancer stem cell therapies.
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PMID:Brain cancer stem cells display preferential sensitivity to Akt inhibition. 1880 38

Hypoxia commonly occurs in solid tumors of the central nervous system (CNS) and often interferes with therapies designed to stop their growth. We found that pediatric high-grade glioma (HGG)-derived precursors showed greater expansion under lower oxygen tension, typical of solid tumors, than normal CNS precursors. Hypoxia inhibited p53 activation and subsequent astroglial differentiation of HGG precursors. Surprisingly, although HGG precursors generated endogenous bone morphogenetic protein (BMP) signaling that promoted mitotic arrest under high oxygen tension, this signaling was actively repressed by hypoxia. An acute increase in oxygen tension led to Smad activation within 30 minutes, even in the absence of exogenous BMP treatment. Treatment with BMPs further promoted astroglial differentiation or death of HGG precursors under high oxygen tension, but this effect was inhibited under hypoxic conditions. Silencing of hypoxia-inducible factor 1alpha (HIF1alpha) led to Smad activation even under hypoxic conditions, indicating that HIF1alpha is required for BMP repression. Conversely, BMP activation at high oxygen tension led to reciprocal degradation of HIF1alpha; this BMP-induced degradation was inhibited in low oxygen. These results show a novel, mutually antagonistic interaction of hypoxia-response and neural differentiation signals in HGG proliferation, and suggest differences between normal and HGG precursors that may be exploited for pediatric brain cancer therapy.
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PMID:Hypoxia and HIF1alpha repress the differentiative effects of BMPs in high-grade glioma. 1883 93

Mitochondria dysfunction and hypoxic microenvironment are hallmarks of cancer cell biology. Recently, many studies have focused on isolation of brain cancer stem cells using CD133 expression. In this study, we investigated whether CD133 expression is regulated by bioenergetic stresses affecting mitochondrial functions in human glioma cells. First, we determined that hypoxia induced a reversible up-regulation of CD133 expression. Second, mitochondrial dysfunction through pharmacological inhibition of the Electron Transport Chain (ETC) produced an up-regulation of CD133 expression that was inversely correlated with changes in mitochondrial membrane potential. Third, generation of stable glioma cells depleted of mitochondrial DNA showed significant and stable increases in CD133 expression. These glioma cells, termed rho(0) or rho(0), are characterized by an exaggerated, uncoupled glycolytic phenotype and by constitutive and stable up-regulation of CD133 through many cell passages. Moreover, these rho(0) cells display the ability to form "tumor spheroids" in serumless medium and are positive for CD133 and the neural progenitor cell marker, nestin. Under differentiating conditions, rho(0) cells expressed multi-lineage properties. Reversibility of CD133 expression was demonstrated by transfering parental mitochondria to rho(0) cells resulting in stable trans-mitochondrial "cybrid" clones. This study provides a novel mechanistic insight about the regulation of CD133 by environmental conditions (hypoxia) and mitochondrial dysfunction (genetic and chemical). Considering these new findings, the concept that CD133 is a marker of brain tumor stem cells may need to be revised.
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PMID:CD133 is a marker of bioenergetic stress in human glioma. 1898 61

The epidermal growth factor receptor (EGFR) is the main tyrosine kinase receptor dysregulated or overexpressed in brain cancer types and its expression is directly correlated with tumor malignancy and unfavorable prognosis. Recently, the availability of endogenous EGFR ligands has been reported to be also regulated indirectly by the activation of several G-protein-coupled receptors (GPCRs) in many cancer cell types. This EGFR transactivation mechanism requires the initial activation of a GPCR that in turn induces the cleavage of membrane-bound EGFR ligands precursors via the involvement of the family of disintegrin and metalloproteases (ADAMs). The discovery of ADAMs in this transactivation mechanism led to the development of small molecule inhibitors. In this minireview we describe the expression of GPCR, ADAMs and EGFR ligands in human glioma brain tumors and the characteristics of small molecule ADAMs inhibitors. The addition of ADAM inhibitors to our pharmacological arsenal could enhance the outcome of combination therapies when using EGFR inhibitors against human brain tumors.
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PMID:Therapeutic targeting of g-protein coupled receptor-mediated epidermal growth factor receptor transactivation in human glioma brain tumors. 1899 57


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