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Gersey, Z.C.; Rodriguez, G.A.; Barbarite, E.; Sanchez, A.; Walters, W.M.; Ohaeto, K.C.; Komotar, R.J.; Graham, R.M. |
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Title |
Curcumin decreases malignant characteristics of glioblastoma stem cells via induction of reactive oxygen species |
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Journal Article |
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Year |
2017 |
Publication |
BMC Cancer |
Abbreviated Journal |
BMC Cancer |
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Volume |
17 |
Issue |
1 |
Pages |
99 |
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Keywords |
Acetylcysteine/pharmacology; Adult; Antineoplastic Agents/*pharmacology; Cell Proliferation/drug effects; Cell Survival/drug effects; Curcumin/*pharmacology; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Free Radical Scavengers; Glioblastoma/drug therapy/pathology; Humans; Inhibitor of Apoptosis Proteins/metabolism; Inhibitory Concentration 50; Mitogen-Activated Protein Kinases/metabolism; Neoplastic Stem Cells/*drug effects; Oxidative Stress; Reactive Oxygen Species/*metabolism; STAT3 Transcription Factor/metabolism; Tumor Cells, Cultured; Brain tumor; Curcumin; Glioblastoma; Natural product; Reactive oxygen species; Stat3; Stem cell |
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Abstract |
BACKGROUND: Glioblastoma Multiforme (GBM) is the most common and lethal form of primary brain tumor in adults. Following standard treatment of surgery, radiation and chemotherapy, patients are expected to survive 12-14 months. Theorized cause of disease recurrence in these patients is tumor cell repopulation through the proliferation of treatment-resistant cancer stem cells. Current research has revealed curcumin, the principal ingredient in turmeric, can modulate multiple signaling pathways important for cancer stem cell self-renewal and survival. METHODS: Following resection, tumor specimens were dissociated and glioblastoma stem cells (GSCs) were propagated in neurosphere media and characterized via immunocytochemistry. Cell viability was determined with MTS assay. GSC proliferation, sphere forming and colony forming assays were conducted through standard counting methods. Reactive oxygen species (ROS) production was examined using the fluorescent molecular probe CM-H2DCFA. Effects on cell signaling pathways were elucidated by western blot. RESULTS: We evaluate the effects of curcumin on patient-derived GSC lines. We demonstrate a curcumin-induced dose-dependent decrease in GSC viability with an approximate IC50 of 25 muM. Treatment with sub-toxic levels (2.5 muM) of curcumin significantly decreased GSC proliferation, sphere forming ability and colony forming potential. Curcumin induced ROS, promoted MAPK pathway activation, downregulated STAT3 activity and IAP family members. Inhibition of ROS with the antioxidant N-acetylcysteine reversed these effects indicating a ROS dependent mechanism. CONCLUSIONS: Discoveries made in this investigation may lead to a non-toxic intervention designed to prevent recurrence in glioblastoma by targeting glioblastoma stem cells. |
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Department of Neurological Surgery, University of Miami Brain Tumor Initiative (UMBTI) Research Laboratory, Lois Pope LIFE Center, 2nd Floor, 1095 NW 14th Terrace, Miami, Florida, 33136, USA. rgraham@med.miami.edu |
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1471-2407 |
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PMID:28160777 |
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Call Number |
ref @ user @ |
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96610 |
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Munthe, S.; Halle, B.; Boldt, H.B.; Christiansen, H.; Schmidt, S.; Kaimal, V.; Xu, J.; Zabludoff, S.; Mollenhauer, J.; Poulsen, F.R.; Kristensen, B.W. |
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Title |
Shift of microRNA profile upon glioma cell migration using patient-derived spheroids and serum-free conditions |
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Journal Article |
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Year |
2017 |
Publication |
Journal of Neuro-Oncology |
Abbreviated Journal |
J Neurooncol |
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132 |
Issue |
1 |
Pages |
45-54 |
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Keywords |
Glioblastoma; MicroRNA; Migration; Serum-free; Target |
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Abstract |
Glioblastoma multiforme (GBM) is the most frequent malignant primary brain tumor. A major reason for the overall median survival being only 14.6 months is migrating tumor cells left behind after surgery. Another major reason is tumor cells having a so-called cancer stem cell phenotype being therefore resistant towards traditional chemo- and radiotherapy. A group of novel molecular targets are microRNAs (miRNAs). MiRNAs are small non-coding RNAs exerting post-transcriptional regulation of gene expression. The aim of this study was to identify differentially expressed miRNAs in migrating GBM cells using serum-free stem cell conditions. We used patient-derived GBM spheroid cultures for a novel serum-free migration assay. MiRNA expression of migrating tumor cells isolated at maximum migration speed was compared with corresponding spheroids using an OpenArray Real-Time PCR System. The miRNA profiling revealed 30 miRNAs to be differentially expressed. In total 13 miRNAs were upregulated and 17 downregulated in migrating cells compared to corresponding spheroids. The three most deregulated miRNAs, miR-1227 (up-regulated), miR-32 (down-regulated) and miR-222 (down-regulated), were experimentally overexpressed. A non-significantly increased migration rate was observed after miR-1227 overexpression. A significantly reduced migration rate was observed after miR-32 and miR-222 overexpression. In conclusion a shift in microRNA profile upon glioma cell migration was identified using an assay avoiding serum-induced migration. Both the miRNA profiling and the functional validation suggested that miR-1227 may be associated with increased migration and miR-32 and miR-222 with decreased migration. These miRNAs may represent potential novel targets in migrating glioma cells. |
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Institute of Clinical Research, University of Southern Denmark, Winslowparken 19, 5000, Odense C, Denmark. bjarne.winther.kristensen@rsyd.dk |
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0167-594X |
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PMID:28091986 |
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ref @ user @ |
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96611 |
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Mistry, A.M.; Dewan, M.C.; White-Dzuro, G.A.; Brinson, P.R.; Weaver, K.D.; Thompson, R.C.; Ihrie, R.A.; Chambless, L.B. |
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Decreased survival in glioblastomas is specific to contact with the ventricular-subventricular zone, not subgranular zone or corpus callosum |
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Journal Article |
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Year |
2017 |
Publication |
Journal of Neuro-Oncology |
Abbreviated Journal |
J Neurooncol |
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Volume |
132 |
Issue |
2 |
Pages |
341-349 |
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Glioblastoma; Stem cells; Subgranular zone; Subventricular zone; Survival; Ventricular-subventricular zone |
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The clinical effect of radiographic contact of glioblastoma (GBM) with neurogenic zones (NZ)-the ventricular-subventricular (VSVZ) and subgranular (SGZ) zones-and the corpus callosum (CC) remains unclear and, in the case of the SGZ, unexplored. We investigated (1) if GBM contact with a NZ correlates with decreased survival; (2) if so, whether this effect is associated with a specific NZ; and (3) if radiographic contact with or invasion of the CC by GBM is associated with decreased survival. We retrospectively identified 207 adult patients who underwent cytoreductive surgery for GBM followed by chemotherapy and/or radiation. Age, preoperative Karnofsky performance status score (KPS), and extent of resection were recorded. Preoperative MRIs were blindly analyzed to calculate tumor volume and assess its contact with VSVZ, SGZ, CC, and cortex. Overall (OS) and progression free (PFS) survivals were calculated and analyzed with multivariate Cox analyses. Among the 207 patients, 111 had GBM contacting VSVZ (VSVZ+GBMs), 23 had SGZ+GBMs, 52 had CC+GBMs, and 164 had cortex+GBMs. VSVZ+, SGZ+, and CC+ GBMs were significantly larger in size relative to their respective non-contacting controls. Multivariate Cox survival analyses revealed GBM contact with the VSVZ, but not SGZ, CC, or cortex, as an independent predictor of lower OS, PFS, and early recurrence. We hypothesize that the VSVZ niche has unique properties that contribute to GBM pathobiology in adults. |
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Department of Neurological Surgery, Vanderbilt University Medical Center, T-4224 Medical Center North, 1161 21st Avenue South, Nashville, TN, 37232-2380, USA |
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0167-594X |
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PMID:28074322 |
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ref @ user @ |
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96612 |
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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. |
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Title |
Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways |
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Journal Article |
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Year |
2017 |
Publication |
Journal of Neurosurgery |
Abbreviated Journal |
J Neurosurg |
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1-12 |
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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 |
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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. |
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Departments of 2 Pharmacology and Toxicology and |
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0022-3085 |
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PMID:28059653 |
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ref @ user @ |
Serial |
96613 |
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Lee, J.W.; Lim, D.H.; Sung, K.W.; Lee, H.J.; Yi, E.S.; Yoo, K.H.; Koo, H.H.; Suh, Y.L.; Shin, H.J. |
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Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for High-Grade Gliomas in Children and Adolescents |
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Journal Article |
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Year |
2017 |
Publication |
Journal of Korean Medical Science |
Abbreviated Journal |
J Korean Med Sci |
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Volume |
32 |
Issue |
2 |
Pages |
195-203 |
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Keywords |
Adolescent; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use; Brain Neoplasms/*drug therapy/mortality/therapy; Carboplatin/administration & dosage; Child; Child, Preschool; Etoposide/administration & dosage; Female; Glioma/*drug therapy/mortality/therapy; Humans; Male; Neoplasm Grading; Remission Induction; Retrospective Studies; Stem Cell Transplantation; Survival Rate; Thiotepa/administration & dosage; Transplantation, Autologous; Treatment Outcome; *Autologous Stem Cell Transplantation; *Brain Tumor; *Children; *High-dose Chemotherapy; *High-grade Glioma |
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With the aim to investigate the outcome of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) for high-grade gliomas (HGGs), we retrospectively reviewed the medical records of 30 patients with HGGs (16 glioblastomas, 7 anaplastic astrocytomas, and 7 other HGGs) between 2006 and 2015. Gross or near total resection was possible in 11 patients. Front-line treatment after surgery was radiotherapy (RT) in 14 patients and chemotherapy in the remaining 16 patients including 3 patients less than 3 years of age. Eight of 12 patients who remained progression free and 5 of the remaining 18 patients who experienced progression during induction treatment underwent the first HDCT/auto-SCT with carboplatin + thiotepa + etoposide (CTE) regimen and 11 of them proceeded to the second HDCT/auto-SCT with cyclophosphamide + melphalan (CyM) regimen. One patient died from hepatic veno-occlusive disease (VOD) during the second HDCT/auto-SCT; otherwise, toxicities were manageable. Four patients in complete response (CR) and 3 of 7 patients in partial response (PR) or second PR at the first HDCT/auto-SCT remained event free: however, 2 patients with progressive tumor experienced progression again. The probabilities of 3-year overall survival (OS) after the first HDCT/auto-SCT in 11 patients in CR, PR, or second PR was 58.2% +/- 16.9%. Tumor status at the first HDCT/auto-SCT was the only significant factor for outcome after HDCT/auto-SCT. There was no difference in survival between glioblastoma and other HGGs. This study suggests that the outcome of HGGs in children and adolescents after HDCT/auto-SCT is encouraging if the patient could achieve CR or PR before HDCT/auto-SCT. |
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Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. shinhj@skku.edu |
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1011-8934 |
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PMID:28049229 |
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ref @ user @ |
Serial |
96614 |
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