| Records |
| Author |
Momeny, M.; Moghaddaskho, F.; Gortany, N.K.; Yousefi, H.; Sabourinejad, Z.; Zarrinrad, G.; Mirshahvaladi, S.; Eyvani, H.; Barghi, F.; Ahmadinia, L.; Ghazi-Khansari, M.; Dehpour, A.R.; Amanpour, S.; Tavangar, S.M.; Dardaei, L.; Emami, A.H.; Alimoghaddam, K.; Ghavamzadeh, A.; Ghaffari, S.H. |
| Title |
Blockade of vascular endothelial growth factor receptors by tivozanib has potential anti-tumour effects on human glioblastoma cells |
Type |
Journal Article |
| Year |
2017 |
Publication |
Scientific Reports |
Abbreviated Journal |
Sci Rep |
| Volume |
7 |
Issue  |
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Pages |
44075 |
| Keywords |
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| Abstract |
Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM. |
| Address |
Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran |
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Place of Publication |
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| Language |
English |
Summary Language |
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Original Title |
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Series Title |
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Abbreviated Series Title |
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| Series Volume |
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Series Issue |
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Edition |
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| ISSN |
2045-2322 |
ISBN |
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Expedition |
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Conference |
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| Notes |
PMID:28287096 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96601 |
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| Author |
Ludwig, K.; Kornblum, H.I. |
| Title |
Molecular markers in glioma |
Type |
Journal Article |
| Year |
2017 |
Publication |
Journal of Neuro-Oncology |
Abbreviated Journal |
J Neurooncol |
| Volume |
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Issue |
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Pages |
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| Keywords |
Glioblastoma; Glioma stem cell; Molecular markers; Mutations; Pathways |
| Abstract |
Gliomas are the most malignant and aggressive form of brain tumors, and account for the majority of brain cancer related deaths. Malignant gliomas, including glioblastoma are treated with radiation and temozolomide, with only a minor benefit in survival time. A number of advances have been made in understanding glioma biology, including the discovery of cancer stem cells, termed glioma stem cells (GSC). Some of these advances include the delineation of molecular heterogeneity both between tumors from different patients as well as within tumors from the same patient. Such research highlights the importance of identifying and validating molecular markers in glioma. This review, intended as a practical resource for both clinical and basic investigators, summarizes some of the more well-known molecular markers (MGMT, 1p/19q, IDH, EGFR, p53, PI3K, Rb, and RAF), discusses how they are identified, and what, if any, clinical relevance they may have, in addition to discussing some of the specific biology for these markers. Additionally, we discuss identification methods for studying putative GSC's (CD133, CD15, A2B5, nestin, ALDH1, proteasome activity, ABC transporters, and label-retention). While much research has been done on these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature. Furthermore, it is unlikely that the investigator will be able to utilize one single marker to prospectively identify and isolate GSC from all, or possibly, any gliomas. |
| Address |
Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA. Hkornblum@mednet.ucla.edu |
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| Language |
English |
Summary Language |
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Original Title |
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Series Title |
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Abbreviated Series Title |
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Series Issue |
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Edition |
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| ISSN |
0167-594X |
ISBN |
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Medium |
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Expedition |
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Conference |
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| Notes |
PMID:28233083 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96605 |
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| Author |
Alshehri, M.M.; Robbins, S.M.; Senger, D.L. |
| Title |
The Role of Neurotrophin Signaling in Gliomagenesis: A Focus on the p75 Neurotrophin Receptor (p75NTR/CD271) |
Type |
Journal Article |
| Year |
2017 |
Publication |
Vitamins and Hormones |
Abbreviated Journal |
Vitam Horm |
| Volume |
104 |
Issue |
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Pages |
367-404 |
| Keywords |
Brain tumor; Cd271; Cancer stem cells; Glioblastoma; Glioma invasion; Nerve growth factor; Neurotrophin; p75(NTR) |
| Abstract |
The p75 neurotrophin receptor (p75NTR, a.k.a. CD271), a transmembrane glycoprotein and a member of the tumor necrosis family (TNF) of receptors, was originally identified as a nerve growth factor receptor in the mid-1980s. While p75NTR is recognized to have important roles during neural development, its presence in both neural and nonneural tissues clearly supports the potential to mediate a broad range of functions depending on cellular context. Using an unbiased in vivo selection paradigm for genes underlying the invasive behavior of glioma, a critical characteristic that contributes to poor clinical outcome for glioma patients, we identified p75NTR as a central regulator of glioma invasion. Herein we review the expanding role that p75NTR plays in glioma progression with an emphasis on how p75NTR may contribute to the treatment refractory nature of glioma. Based on the observation that p75NTR is expressed and functional in two critical glioma disease reservoirs, namely, the highly infiltrative cells that evade surgical resection, and the radiation- and chemotherapy-resistant brain tumor-initiating cells (also referred to as brain tumor stem cells), we propose that p75NTR and its myriad of downstream signaling effectors represent rationale therapeutic targets for this devastating disease. Lastly, we provide the provocative hypothesis that, in addition to the well-documented cell autonomous signaling functions, the neurotrophins, and their respective receptors, contribute in a cell nonautonomous manner to drive the complex cellular and molecular composition of the brain tumor microenvironment, an environment that fuels tumorigenesis. |
| Address |
Arnie Charbonneau Cancer Centre, University of Calgary, Calgary, AB, Canada. Electronic address: senger@ucalgary.ca |
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English |
Summary Language |
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Original Title |
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Series Title |
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Abbreviated Series Title |
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Series Issue |
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Edition |
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| ISSN |
0083-6729 |
ISBN |
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Expedition |
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Conference |
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| Notes |
PMID:28215302 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96606 |
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| Author |
Bijangi-Vishehsaraei, K.; Reza Saadatzadeh, M.; Wang, H.; Nguyen, A.; Kamocka, M.M.; Cai, W.; Cohen-Gadol, A.A.; Halum, S.L.; Sarkaria, J.N.; Pollok, K.E.; Safa, A.R. |
| Title |
Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways |
Type |
Journal Article |
| Year |
2017 |
Publication |
Journal of Neurosurgery |
Abbreviated Journal |
J Neurosurg |
| Volume |
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Issue |
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Pages |
1-12 |
| Keywords |
CCCP = carbonyl cyanide m-chlorophenylhydrazone; DMSO = dimethyl sulfoxide; DSB = double-strand break; EGF = epidermal growth factor; FACS = fluorescence-activated cell sorting; FGF = fibroblast growth factor; GBM = glioblastoma; GSC = glioblastoma stem cell; IC50 = 50% inhibition of cell survival; MRC = mitochondrial respiratory chain; MSC = mesenchymal stromal cell; NAC = N-acetylcysteine; NSG = nonobese diabetic scid gamma; PE = phycoerythrin; ROS = reactive oxygen species; SFN = sulforaphane; SSB = single-strand break; apoptosis; cancer stem cells; glioblastoma; oncology; sulforaphane |
| Abstract |
OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)-a constituent of cruciferous vegetables with a multitargeted effect-as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of gamma-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell-induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy. |
| Address |
Departments of 2 Pharmacology and Toxicology and |
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English |
Summary Language |
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Original Title |
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Series Title |
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Abbreviated Series Title |
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Series Issue |
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Edition |
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0022-3085 |
ISBN |
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Conference |
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| Notes |
PMID:28059653 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96613 |
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| Author |
Clark, P.A.; Gaal, J.T.; Strebe, J.K.; Pasch, C.A.; Deming, D.A.; Kuo, J.S.; Robins, H.I. |
| Title |
The effects of tumor treating fields and temozolomide in MGMT expressing and non-expressing patient-derived glioblastoma cells |
Type |
Journal Article |
| Year |
2017 |
Publication |
Journal of Clinical Neuroscience : Official Journal of the Neurosurgical Society of Australasia |
Abbreviated Journal |
J Clin Neurosci |
| Volume |
36 |
Issue |
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Pages |
120-124 |
| Keywords |
Antineoplastic Agents, Alkylating/*pharmacology; Cell Line, Tumor; Cell Proliferation/drug effects/radiation effects; Cell Survival/drug effects/radiation effects; Cells, Cultured; DNA Modification Methylases/genetics/*metabolism; DNA Repair Enzymes/genetics/*metabolism; Dacarbazine/*analogs & derivatives/pharmacology; *Electromagnetic Fields; Glioblastoma/genetics/*metabolism; Humans; Neoplastic Stem Cells/drug effects/radiation effects; Neurons/drug effects/radiation effects; Tumor Suppressor Proteins/genetics/*metabolism; Cancer stem cells; Glioblastoma; MGMT methylation; Temozolomide; Tumor treating fields |
| Abstract |
A recent Phase 3 study of newly diagnosed glioblastoma (GBM) demonstrated the addition of tumor treating fields (TTFields) to temozolomide (TMZ) after combined radiation/TMZ significantly increased survival and progression free survival. Preliminary data suggested benefit with both methylated and unmethylated O-6-methylguanine-DNA methyl-transferase (MGMT) promoter status. To date, however, there have been no studies to address the potential interactions of TTFields and TMZ. Thus, the effects of TTFields and TMZ were studied in vitro using patient-derived GBM stem-like cells (GSCs) including MGMT expressing (TMZ resistant: 12.1 and 22GSC) and non-MGMT expressing (TMZ sensitive: 33 and 114GSC) lines. Dose-response curves were constructed using cell proliferation and sphere-forming assays. Results demonstrated a 10-fold increase in TMZ resistance of MGMT-expressing (12.1GSCs: IC50=160muM; 22GSCs: IC50=44muM) compared to MGMT non-expressing (33GSCs: IC50=1.5muM; 114GSCs: IC50=5.2muM) lines. TTFields inhibited 12.1 GSC proliferation at all tested doses (50-500kHz) with an optimal frequency of 200kHz. At 200kHz, TTFields inhibited proliferation and tumor sphere formation of both MGMT GSC subtypes at comparable levels (12.1GSC: 74+/-2.9% and 38+/-3.2%, respectively; 22GSC: 61+/-11% and 38+/-2.6%, respectively; 33GSC: 56+/-9.5% and 60+/-7.1%, respectively; 114 GSC: 79+/-3.5% and 41+/-4.3%, respectively). In combination, TTFields (200kHz) and TMZ showed an additive anti-neoplastic effect with equal efficacy for TTFields in both cell types (i.e., +/- MGMT expression) with no effect on TMZ resistance. This is the first demonstration of the effects of TTFields on cancer stem cells. The expansion of such studies may have clinical implications. |
| Address |
University of Wisconsin Carbone Cancer Center, UWSMPH, United States; Division of Hematology and Oncology, Department of Medicine, UWSMPH, United States; William S Middleton Memorial Veterans Hospital, Madison, WI, United States; Department of Neurology, UWSMPH, United States; Department of Human Oncology, UWSMPH, United States. Electronic address: hirobins@wisc.edu |
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English |
Summary Language |
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Original Title |
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Series Title |
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Abbreviated Series Title |
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Series Issue |
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Edition |
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| ISSN |
0967-5868 |
ISBN |
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Medium |
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| Area |
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Expedition |
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Conference |
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| Notes |
PMID:27865821 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96622 |
| Permanent link to this record |
