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)

Mutations that may predict response to adenosine 5'-triphosphate (ATP)-mimetic epidermal growth factor receptor (EGFR) inhibitors occur in the EGFR kinase domain in lung adenocarcinomas and bronchioloalveolar carcinomas (BACs). Data on the frequency of EGFR mutations are sparse in other human tumors. Apart from the deletion mutant EGFRvIII, little is known about the frequency of mutations that encode for the EGFR extracellular domains II and IV that participate in receptor dimerization and formation of the tethered (autoinhibited) receptor conformation. We investigated 566 human neoplasms consisting of various histological types for mutations in exons 6, 7 (encode domain II), 14, 15 (domain IV), 18, 19, and 21 (the kinase domain) using denaturing high-performance liquid chromatography (DHPLC). Approximately 4,500 EGFR exons were screened for the presence of a mutation, and samples with an abnormal finding in DHPLC were sequenced. Only one mutation was found in the extracellular domain IV (glioblastoma), and none in domain II. Eight (11%) out of the 40 lung adenocarcinomas, or 33 BACs, investigated had exon 19 or 21 mutation in the kinase domain, but no mutations were found in other tumor types. Most of the lung cancers with mutated EGFR had three to six copies of the mutated gene in fluorescence in situ hybridization. We conclude that mutations of the EGFR kinase domain and the cysteine-rich extracellular domains are infrequent in most types of human cancer apart from lung adenocarcinoma. Mutated EGFR is usually not amplified in lung cancer.
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PMID:Epidermal growth factor receptor domain II, IV, and kinase domain mutations in human solid tumors. 1613 19

Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of alkynamide analogues of quinazoline- and pyrido[3,4-d]pyrimidine-based compounds. The compounds were prepared by coupling the appropriate 6-aminoquinazolines or 6-aminopyrido[3,4-d]pyrimidines with alkynoic acids, using EDCI.HCl in pyridine. The compounds showed pan-erbB enzyme inhibition but were on average about 10-fold more potent against erbB1 than against erbB2 and erbB4. For cellular inhibition, the nature of the alkylating side chains was an important determinant, with 5-dialkylamino-2-pentynamide type Michael acceptors providing the highest potency. This is suggested to be due to an improved ability of the amine to participate in an autocatalysis of the Michael reaction with enzyme cysteine residues. Pyrido[3,4-d]pyrimidine analogue 39 was selected for in vivo evaluation and achieved tumor regressions at 10 mg/kg in the A431 human epidermoid carcinoma and at 40 mg/kg for the SF767 human glioblastoma and the SKOV3 human ovarian carcinoma. Complete stasis was observed at 40 mg/kg in the BXPC3 human pancreatic carcinoma as well as in the H125 human non-small-cell lung carcinoma.
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PMID:Tyrosine kinase inhibitors. 19. 6-Alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB family of tyrosine kinase receptors. 1648 Feb 84

Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.
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PMID:TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells. 1662 57

Azurin is a periplasmic 128 amino acid protein in Pseudomonas aeruginosa, termed Paz, which has been shown to enter preferentially and induce apoptosis in cancer cells such as human melanoma or breast cancer. Its effectiveness against brain tumors such as glioblastomas has not been studied. The meningitis-causing bacterium Neisseria meningitidis also harbors an azurin-like protein. Unlike all other known azurins, Neisserial azurin, termed Laz, is surface-exposed and has in its N-terminal region a 39 amino acid epitope called H.8. Upstream of this H.8 moiety is a lipobox that results in the truncation of the protein at the N-terminal cysteine residue with modification by a lipid group. No function of Laz is known. We demonstrate that while Paz is deficient in entering glioblastoma cells and exhibits low cytotoxicity, Laz is much more proficient in entering glioblastoma cells and shows a higher level of cytotoxicity. When the Neisserial H.8 moiety containing the lipobox is fused in frame with Paz either in its N-terminal (H.8-Paz) or in its C-terminal (Paz-H.8), both had high cytotoxicity for glioblastoma cells and a higher level of internalization. When expressed in E. coli, H.8-Paz was much more exposed on the surface than Paz-H.8. The replacement of the Laz N-terminal cysteine residue involved in acylation with an alanine residue abolished the surface display, but had no effect on cytotoxicity or entry in glioblastoma cells, suggesting a role of the H.8 moiety, but not its lipidation, in disrupting the entry barrier in brain tumor cells.
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PMID:Disrupting the entry barrier and attacking brain tumors: the role of the Neisseria H.8 epitope and the Laz protein. 1686 7

We investigate the cytotoxic effect of metal protoporphyrins including ferric protoporphyrin (FePP; hemin), cobalt protoporphyrin (CoPP), and tin protoporphyrin (SnPP) in glioblastoma cells C6 and GBM8401. Data of MTT assay show that FePP and CoPP, but not SnPP, significantly reduce the viability of glioma cells C6 and GBM8401 in the absence of serum. In the condition with fetal bovine serum (FBS) or bovine serum albumin (BSA), the cytotoxic effect of FePP and CoPP was completely inhibited. Binding of FePP, CoPP, and SnPP with BSA was examined via spectrophotometer analysis, and the protective effect of serum against FePP and CoPP-induced cell death was abolished by BSA depletion. A loss in the integrity of DNA with an occurrence of apoptotic events including DNA ladders, caspase 3 and PARP protein cleavage, and chromatin-condensed cells is observed in FePP-treated or CoPP-treated C6 cells. An increase in intracellular peroxide level was examined in FePP, but not CoPP, -treated C6 cells, and N-acetyl-l-cysteine (NAC) addition significantly protected C6 cells from FePP, but not CoPP, -induced cell death with reducing FePP-stimulated reactive oxygen species (ROS) production. Activation of extracellular regulated kinases (ERKs) and c-Jun-N-terminal kinases (JNKs) with an increase in the heme oxygenase-1 (HO-1) protein was observed in FePP-treated or CoPP-treated C6 cells in the absence of FBS or BSA, and adding JNKs inhibitor SP600125 (SP), but not ERKs inhibitor PD98059 (PD), significantly attenuated FePP-induced or CoPP-induced HO-1 protein expression in accordance with reducing JNKs protein phosphorylation. However, PD98059, SP600125, or transfection of C6 cells with antisense HO-1 oligonucleotides show no effect on the cytotoxicity elicited by FePP and CoPP in C6 cells. Effect of serum and BSA on the cytotoxicity of metal protoporphyrins in glioma cells is first demonstrated in the present study, and the roles of ROS, MAPKs, and HO-1 were elucidated.
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PMID:Cytotoxic effects of metal protoporphyrins in glioblastoma cells: roles of albumin, reactive oxygen species, and heme oxygenase-1. 1828 2

Toxic cyanobacterial blooms are a rich source of metabolites having a variety of biological activities. Two main groups of cyclic peptides, depsipeptides and ureido linkage-containing peptides, reportedly inhibit serine peptidases. We characterised their inhibitory properties against selected peptidases and investigated their influence on cell viability. The depsipeptide planktopeptin BL1125 is a strong linear competitive tight-binding inhibitor of leukocyte (K(i)=2.9 nm) and pancreatic (K(i)=7.2 nm) elastase and also of chymotrypsin (K(i)=6.1 nm). Anabaenopeptins B and F show no inhibition against chymotrypsin, but inhibit both elastases. The tested cyclic peptides do not inhibit trypsin, urokinase, kallikrein 1 or cysteine peptidases. All three tested cyanopeptides show no short-term cytotoxicity in concentrations of up to 10 mum, but impair the metabolic activity of normal human astrocytes after prolonged exposure (48-96 h), whereas glioblastoma cells, tumour cells of the same type, are resistant. Strong inhibition and relative selectivity of the tested cyanopeptides suggests that they are potential candidates for application in inflammatory diseases and possibly some types of cancers.
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PMID:Cytotoxic and peptidase inhibitory activities of selected non-hepatotoxic cyclic peptides from cyanobacteria. 1871 22

Glioblastoma grows aggressively due to its ability to maintain abnormally high potentials for cell proliferation. The present study examines the synergistic actions of N-(4-hydroxyphenyl) retinamide (4-HPR) and paclitaxel (PTX) to control the growth of rat glioblastoma C6 and RG2 cell lines. 4-HPR induced astrocytic differentiation that was accompanied by increased expression of the tight junction protein e-cadherin and sustained down regulation of Id2 (member of inhibitor of differentiation family), catalytic subunit of rat telomerase reverse transcriptase (rTERT), and proliferating cell nuclear antigen (PCNA). Flow cytometric analysis showed that the microtubule stabilizer PTX caused cell cycle deregulation due to G2/M arrest. This in turn could alter the fate of kinetochore-spindle tube dynamics thereby halting cell cycle progression. An interesting observation was the induction of G1/S arrest by a combination of 4-HPR and PTX, altering the G2/M arrest induced by PTX alone. This was further ratified by the upregulation of tumor suppressor protein retinoblastoma, which repressed the expression of the key signaling moieties to induce G1/S arrest. Collectively, the combination of 4-HPR and PTX diminished the survival factors (e.g., rTERT, PCNA, and Bcl-2) to make glioblastoma cells highly prone to apoptosis with activation of cysteine proteases (e.g., calpain, cathepsins, caspase-8, caspase-3). Hence, the combination of 4-HPR and PTX can be considered as an effective therapeutic strategy for controlling the growth of heterogeneous glioblastoma cell populations.
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PMID:N-(4-Hydroxyphenyl) retinamide potentiated paclitaxel for cell cycle arrest and apoptosis in glioblastoma C6 and RG2 cells. 1928 47

Cells that migrate away from a central tumour into brain tissue are responsible for inefficient glioblastoma treatment. This migratory behaviour depends partially on lysosomal cysteine cathepsins. Reportedly, the expression of cathepsins B, L and S gradually increases in the progression from benign astrocytoma to the malignant glioblastoma, although their specific roles in glioma progression have not been revealed. The aim of this study was to clarify their specific contribution to glioblastoma cell invasion. The differences between the matrix invading cells and non-invading core cells from spheroids derived from glioblastoma cell culture and from glioblastoma patients' biopsies, and embedded in type I collagen, have been studied at the mRNA, protein and cathepsin activity levels. Analyses of the two types of cells showed that the three cathepsins were up-regulated post-translationally, their specific activities increasing in the invading cells. The cystatin levels were also differentially altered, resulting in higher ratio of cathepsins B and L to stefin B in the invading cells. However, using specific synthetic inhibitors and silencing strategies revealed that only cathepsin B activity was involved in the invasion of glioblastoma cells, confirming previous notion of cathepsin B as tumour invasiveness biomarker. Our data support the concept of specific roles of cysteine cathepsins in cancer progression. Finally the study points out on the complexity of protease regulation and the need to include functional proteomics in the systems biology approaches to understand the processes associated with glioma invasion and progression.
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PMID:Post-translational regulation of cathepsin B, but not of other cysteine cathepsins, contributes to increased glioblastoma cell invasiveness in vitro. 1943 18

A disintegrin and metalloproteinase 19 (ADAM19, or adamalysin 19) is a cell surface glycoprotein with a signal sequence, a prodomain, a metalloproteinase domain, a disintegrin domain, a cysteine-rich domain, a epidermal growth factor-like domain, a transmembrane domain, and a cytoplasmic domain. It is an endopeptidase that cleaves extracellular matrix proteins and sheds growth factors and cytokines such as neuregulins, heparin-binding epidermal growth factor, tumor necrosis factor (TNF)-alpha, and TNF-related activation-induced cytokine. The ADAM19 gene was cloned from human, monkey, and mouse. It is expressed in multiple organs and tissues including heart, lung, bones, brain, spleen, liver, skeletal muscle, kidney, and testes. ADAM19 plays essential roles in embryo implantation, cardiovascular morphogenesis, neurogenesis, and other developmental processes. It has constitutive alpha-secretase activity associated with processing Alzheimer's disease amyloid precursor protein (APP) to non-amyloidogenic fragments; thus, it is neuroprotective. Those observations indicate that inhibition of ADAM19 activity is undesirable during embryo development and morphogenesis, and during the development of Alzheimer's disease. On the contrary, in adults, ADAM19 is upregulated in human brain tumors such as astrocytoma and glioblastoma and is correlated with the invasiveness of glioma. It is also over-expressed by many human cancerous cell lines including cancers of the colon, ovary, lung, and brain. Abnormally high expression of ADAM19 is also linked to inflammation and fibrosis of the lung and kidney. Targeted inhibition of ADAM19 may be crucial for the treatment of certain types of tumors and inflammatory diseases.
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PMID:ADAM19/adamalysin 19 structure, function, and role as a putative target in tumors and inflammatory diseases. 1960 35

Malignant glioma is characterized by rapid proliferation, high invasiveness into the surrounding brain and increased vascularity. The aim of the study was to explain the observation that glioblastoma invasion often occurs along existing vasculature, suggesting interactions between the two types of cells. Using the in vitro model, we demonstrate that co-culturing of U87 (human glioblastoma) cells with HMEC-1 (human microvascular endothelial) cells increases the invasiveness of the U87 cells. The enhanced invasiveness correlates with increased expression of MMP-9 in both U87 and HMEC-1 cells, increased expression of cysteine cathepsins B and S and down-regulation of endogenous cell adhesion molecule NCAM in U87 cells. On the other hand, U87 tumour cells significantly enhance the proliferation of co-cultured endothelial cells by a mechanism involving cathepsin B, but not cathepsin S. Furthermore, we demonstrated that increased cell expression and activity of MMP-9 in cell microenvironment is mediated via secretion of SDF-1 by HMEC-1 cells. Selective SDF-1 inhibition impaired the enhanced U87 cell invasion, mostly via down-regulation of MMP-9, but did not alter cathepsin B, although the latter is more relevant for the invasion of U87 cells in mono-culture. Taken together, our study suggests that glioblastoma cells may be attracted by endothelial cells, enhancing their proliferation and underlines the importance of SDF-1, cathepsin B and MMP-9 in the cross-talk between these cells in normoxic conditions. This notion contributes to better understanding and suggests further investigations of the paracrine mechanisms, regulating glioma angiogenesis.
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PMID:Glioblastoma and endothelial cells cross-talk, mediated by SDF-1, enhances tumour invasion and endothelial proliferation by increasing expression of cathepsins B, S, and MMP-9. 1970 Feb 39


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