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)

In this study, we present in vitro cytotoxicity of iron oxide (Fe(3)O(4)) and manganese oxide (MnO) using live/dead cell assay, lactate dehydrogenase assay, and reactive oxygen species detection with variation of the concentration of nanoparticles (5-500 microg/ml), incubation time (18-96 h), and different human cell lines (lung adenocarcinoma, breast cancer cells, and glioblastoma cells). The surface of nanoparticles is modified with polyethyleneglycol-derivatized phospholipid to enhance the biocompatibility, water-solubility, and stability under an aqueous media. While the cytotoxic effect was negligible for 18 h incubation even at highest concentration of 500 microg/ml, MnO nanoparticle represented higher level of toxicity than those of Fe(3)O(4) and the commercial medical contrast reagent, Feridex after 2 and 4 day incubation time. However, the cytotoxicity of Fe(3)O(4) is equivalent or better than Feridex based on the live/dead cell viability assay. The engineered MnO and Fe(3)O(4) exhibited excellent stability compared with Feridex for a prolonged incubation time.
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PMID:In vitro cytotoxicity screening of water-dispersible metal oxide nanoparticles in human cell lines. 1963 92

Glioblastomas are highly lethal cancers that contain cellular hierarchies with self-renewing cancer stem cells that can propagate tumors in secondary transplant assays. The potential significance of cancer stem cells in cancer biology has been demonstrated by studies showing contributions to therapeutic resistance, angiogenesis and tumor dispersal. We recently reported that physiologic oxygen levels differentially induce hypoxia inducible factor-2alpha (HIF2alpha) levels in cancer stem cells. HIF1alpha functioned in proliferation and survival of all cancer cells but also was activated in normal neural progenitors suggesting a potentially restricted therapeutic index while HIF2alpha was essential in only in cancer stem cells and was not expressed by normal neural progenitors demonstrating HIF2alpha is a cancer stem cell specific target. We now extend these studies to examine the role of hypoxia in regulating tumor cell plasticity. We find that hypoxia promotes the self-renewal capability of the stem and non-stem population as well as promoting a more stem-like phenotype in the non-stem population with increased neurosphere formation as well as upregulation of important stem cell factors, such as OCT4, NANOG and c-MYC. The importance of HIF2alpha was further supported as forced expression of non-degradable HIF2alpha induced a cancer stem cell marker and augmented the tumorigenic potential of the non-stem population. This novel finding may indicate a specific role of HIF2alpha in promoting glioma tumorigenesis. The unexpected plasticity of the non-stem glioma population and the stem-like phenotype emphasizes the importance of developing therapeutic strategies targeting the microenvironmental influence on the tumor in addition to cancer stem cells.
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PMID:The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype. 1977 May 85

Danthron (1,8-dihydroxyanthraquinone), is one of component from Rheum palmatum L. (Polygonaceae), has been shown several biological activities but did not show to induce apoptosis in human brain tumor cells. The aim of this study is to investigate the mechanisms by danthron for the induction of apoptotic potential on human brain glioblastoma multiforms GBM 8401 cell line. Danthron showed a marked concentration- and time-dependent inhibition of GBM 8401 cell viability and induced apoptosis in a dose-and time-dependent manner. There was an attenuation of mitochondrial membrane potential (DeltaPsi(m)) with the alterations of Bcl-2/Bax protein ratio in GBM 8401 cells, indicating the participation of a mitochondria-related mechanism. Pretreatment of a caspase-8 inhibitor (Z-IETD-FMK), caspase-9 inhibitor (Z-LEHD-FMK) and caspase-3 inhibitor (Z-DEVE-FMK) significantly increased the viable of GBM 8401 cells implied that the participations of caspases. Western blotting analysis also showed the activation of initiator caspase-8 and caspase-9, and executor caspase-3 in GBM 8401 cells. Meanwhile, danthron also promoted the generation of reactive oxygen species (ROS) and cytosolic Ca(2+) in GBM 8401 cells. Taken together, our data showed that danthron induced apoptosis in GBM 8401 cells through mitochondria-related and caspase-related pathways, and it may be further evaluated as a chemotherapeutic agent for human brain cancer.
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PMID:Danthron induced apoptosis through mitochondria- and caspase-3-dependent pathways in human brain glioblastoma multiforms GBM 8401 cells. 1978 69

Inflammation which is an indispensable participant in tumor progression is intricately linked with redox modulation. The pro-inflammatory cytokine Tumor Necrosis Factor (TNFalpha) elevates reactive oxygen species (ROS) in glioblastoma multiforme (GBM). As both TNFalpha and oxidative stress independently play role in regulating cytoskeletal organization and cell survival pathways we investigated whether TNFalpha mediated oxidative stress regulates responses that offer survival advantages to glioblastoma cells. Treatment with TNFalpha elevated Akt phosphorylation in glioma cells. Increased in Akt phosphorylation was concurrent with the decrease in ROS scavenger SOD-1 levels. TNFalpha mediated increase in Akt phosphorylation was dependent on oxidative stress as Akt phosphorylation was abrogated in the presence of ROS inhibitor and elevated in cells transfected with SOD-1 siRNA. TNFalpha altered actin cytoskeletal organization and increased Cdc42 levels. This increase in Cdc42 was concomitant with its increased interaction with scaffold protein IQGAP-1. Also, we report for the first time a ROS dependent interaction between pAkt and IQGAP-1 in TNFalpha treated cells. Importantly, Akt inhibition not only reversed TNFalpha mediated changes in actin cytoskeletal organization but also abrogated anchorage independent growth. Together, these results suggest that TNFalpha induced oxidative stress affects Akt activation to regulate actin organization and growth of glioma cells.
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PMID:TNFalpha induced oxidative stress dependent Akt signaling affects actin cytoskeletal organization in glioma cells. 1983 30

On the basis of not only the endosymbiotic theory of eukaryotic cell organization and evolution but also of observations of transcellular communication via Tunneling NanoTubes (TNTs), the hypothesis is put forward that when mitochondria, which were once independently living prokaryote-like organisms, are subjected to detrimental genetic, toxic, or environmental conditions, including age-related endogenous factors, they can regress towards their original independent state. At that point, they can become potentially pathogenic intruders within their eukaryotic host cell. Because of the protoplasmic disequilibrium caused by an altered, or mutated, mitochondral population, certain host cells with a minimal capacity for self-renewal, such as dopaminergic neurons, risk a loss of function and degenerate. It is also proposed that altered mitochondria, as well as their mutated mtDNA, can migrate, via TNTs, into adjacent cells. In this way, neurodegenerative states are propagated between cells (glia and/or neurons) of the Central Nervous System (CNS) and that this leads to conditions such as Alzheimer's and Parkinson's disease. This proposal finds indirect support from observations on rotenone-poisoned glioblastoma cells which have been co-cultured with non-poisoned cells. Immunocytochemical techniques revealed that mitochondria, moving along the TNTs, migrated from the poisoned cells towards the healthy cells. It has also been demonstrated by means of immunocytochemistry that, in glioblastoma cell cultures, Amyloid Precursor Protein (APP) is present in TNTs, hence it may migrate from one cell to neighbouring cells. This datum may be of high relevance for a better understanding of Alzheimer's Disease (AD) since molecular, cellular, and animal model studies have revealed that the formation of amyloid beta (Abeta) and other derivatives of the APP are key pathogenic factors in AD, causing mitochondrial dysfunction, free radical generation, oxidative damage, and inflammation. Furthermore, the present data demonstrate the presence of alpha-synuclein (alpha-syn) within TNTs, hence a similar pathogenic mechanism to the one surmised for AD, but centred on alpha-syn rather than on Abeta, may play a role in Parkinson's Disease (PD). As a matter of fact, alpha-syn can enter mitochondria and interact with complex I causing respiratory deficiency and increased oxygen free radical production. In agreement with this view, it has been demonstrated that, in comparison with normal subjects, PD patients show a significant accumulation of alpha-syn at Substantia Nigra and Striatal level, predominantly associated with the inner mitochondrial membrane,. These observations suggest that potentially neuropathogenic proteins, such as Abeta and alpha-syn, can not only diffuse via the extracellular space but also move from cell to cell also via TNTs where they can cause mitochondrial damage and cell degeneration. A mathematical model (see Appendix) is proposed to simulate the pathogenic consequences of the migration of altered mitochondria and/or of their mtDNA via TNTs. The results of the present simulation is compatible with the proposal that mutated mitochondrial agents behave as though they were infectious particles migrating through a continuum of interconnected cells.
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PMID:A new hypothesis of pathogenesis based on the divorce between mitochondria and their host cells: possible relevance for Alzheimer's disease. 1986 Jul 24

Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal isoform of the prion protein PrP(Sc). Human prion protein fragment, PrP (106-126) (prion protein peptide 106-126), may contain most of the pathological features associated with PrP(Sc). Hypoxic conditions elicit cellular responses adaptively designed to improve cell survival and have an important role in the process of cell survival. We investigate the effects of hypoxia on PrP (106-126)-induced apoptosis in the present study. Human neuroblastoma and glioblastoma cells were incubated with varied doses of PrP (106-126) under both normoxic or hypoxic conditions, in order to determine the regulatory effects of hypoxia on PrP (106-126)-induced apoptosis. The results indicate that hypoxia protects neuronal cells against PrP (106-126)-induced cell death by activating the Akt signal, which is inactivated by prion proteins, and inhibiting PrP (106-126)-induced caspase 3 activation. Low oxygen conditions increase the Bcl-2 protein, which is associated with anti-apoptotic signals, and recover the PrP (106-126)-induced reduction in mitochondrial transmembrane potential. This study demonstrates that hypoxia inhibits PrP (106-126)-induced neuron cell death by regulating Akt and Akt-related signaling, and it also suggests that prion-related neuronal damage and disease may be regulated by hypoxia or by hypoxic-inducing genes.
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PMID:Hypoxia protects neuronal cells from human prion protein fragment-induced apoptosis. 1991 74

Cancer development is a multistep process, driven by a series of genetic and environmental alterations, that endows cells with a set of hallmark traits required for tumorigenesis. It is broadly accepted that growth signal autonomy, the first hallmark of malignancies, can be acquired through multiple genetic mutations that activate an array of complex, cancer-specific growth circuits [Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57-70; Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789-799]. The superfluous nature of these pathways is thought to severely limit therapeutic approaches targeting tumor proliferation, and it has been suggested that this strategy be abandoned in favor of inhibiting more systemic hallmarks, including angiogenesis (Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: Mechanisms of anti-tumor activity. Nat Rev Cancer 8:579-591; Stommel JM, et al. (2007) Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290; Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727-739; Kaiser J (2008) Cancer genetics: A detailed genetic portrait of the deadliest human cancers. Science 321:1280-1281]. Here, we report the unexpected observation that genetically diverse cancers converge at a common and obligatory growth axis instigated by HIF-2alpha, an element of the oxygen-sensing machinery. Inhibition of HIF-2alpha prevents the in vivo growth and tumorigenesis of highly aggressive glioblastoma, colorectal, and non-small-cell lung carcinomas and the in vitro autonomous proliferation of several others, regardless of their mutational status and tissue of origin. The concomitant deactivation of select receptor tyrosine kinases, including the EGFR and IGF1R, as well as downstream ERK/Akt signaling, suggests that HIF-2alpha exerts its proliferative effects by endorsing these major pathways. Consistently, silencing these receptors phenocopies the loss of HIF-2alpha oncogenic activity, abrogating the serum-independent growth of human cancer cells in culture. Based on these data, we propose an alternative to the predominant view that cancers exploit independent autonomous growth pathways and reveal HIF-2alpha as a potentially universal culprit in promoting the persistent proliferation of neoplastic cells.
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PMID:Human cancers converge at the HIF-2alpha oncogenic axis. 1995 13

Molecular oxygen is the best known mediator of radiation damage during radiation therapy. This paper investigates techniques for enhancing tumor oxygenation by use of anti-angiogenic therapy for better radiosensitivity. A noninvasive monitoring technique, Acoustic radiation force (ARF)-induced optical spectroscopy, was proposed in this paper to track tumor oxygen changes during anti-angiogenic therapy. Male NCR-NUM nude mice bearing human U87 glioblastoma (ATCC) xenografts on the right hind limb were used for the study. An anti-angiogenic regimen using the drug AZD2171 (AsraZeneca) was found capable of improving tissue oxygenation during the first week of drug treatment. The optical spectroscopy technique was shown to be able to track tumor oxygenation changes during anti-angiogenic therapy, as verified by direct pO2 measurement. By using anti-angiogenic therapy to improve tumor oxygenation prior to radiotherapy, tissue oxygenation may be altered in a way that favors radiation therapy.
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PMID:Acoustic radiation force and optical spectroscopy for assessing tumor vessel normalization during anti-angiogenic therapy. 1996 40

Adaptive responses to hypoxia in tumors are transcriptionally regulated by the hypoxia inducible factors (HIF-1alpha/HIF-2alpha), which are tightly controlled by the HIF-prolyl hydroxylases (PHD). Hypoxia induces expression of the PHD2 and PHD3 proteins in tumors but the pathobiological significance of these events is uncertain. Here, we show that PHD2 and PHD3 induction acts within a negative feedback loop to limit the hypoxic HIF response. In glioblastomas, PHD2 and PHD3 are hypoxia-inducible in vitro and expressed in hypoxic areas of tumors in vivo. Comparison with other PHDs revealed distinct cytoplasmatic and nuclear localization patterns of PHD2 and PHD3. Gain and loss of function experiments defined PHD2 and PHD3 as HIF target genes that remained operative even at low oxygen concentrations. We found that increased PHD levels could compensate for reduced oxygen availability to regulate the HIF response. This negative feedback loop protected tumor cells against hypoxia-induced cell death, functionally implicating this pathway in the control of the tumor-suppressive components of the HIF system in glioblastoma. Moreover, PHD inhibition facilitated cell death induction by staurosporine or tumor necrosis factor-related apoptosis-inducing ligand, hinting at a more general protective role of PHD in the regulation of cell viability. In summary, our findings recognize the PHD/HIF regulatory axis as a novel therapeutic target to disable a tumor's ability to adjust to hypoxic conditions and control cell survival, helping to potentially overcome therapeutic cell death resistance in glioblastomas.
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PMID:Prolyl hydroxylases 2 and 3 act in gliomas as protective negative feedback regulators of hypoxia-inducible factors. 2002 63

Clinical trials have revealed that N-(4-hydroxyphenyl) retinamide (4HPR; fenretinide), a synthetic retinoic acid derivative, is a highly active and promising therapeutic and chemopreventive agent. Fenretinide shows biological activity against numerous cancer types in vitro and in preclinical studies. Clinical trials have shown that fenretinide induces a significant reduction of second breast cancer in premenopausal women. Several studies on different neoplasms are ongoing, such as breast and ovarian cancer, neuroblastoma, glioblastoma, head and neck and skin cancers and others. It has minimal side effects in humans, so that trials in young women at high-risk of breast cancer and ovarian and for the prevention of other tumor types such as lung cancer could be envisaged. Here we review some ongoing clinical trials and evaluate the possible mechanisms underlying the secondary chemopreventive effects of 4HPR. In particular we report basic and translational data on the anti-angiogenic "angiopreventive" properties of fenretinide, its anti-invasive activity, its ability to induce apoptosis and to generate or enhance production of reactive oxygen species as possible molecular bases for a chemopreventive action in patients.
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PMID:Angioprevention with fenretinide: targeting angiogenesis in prevention and therapeutic strategies. 2003 9


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