| Records |
| Author |
Sareddy, G.R.; Viswanadhapalli, S.; Surapaneni, P.; Suzuki, T.; Brenner, A.; Vadlamudi, R.K. |
| Title |
Novel KDM1A inhibitors induce differentiation and apoptosis of glioma stem cells via unfolded protein response pathway |
Type |
Journal Article |
| Year |
2017 |
Publication |
Oncogene |
Abbreviated Journal |
Oncogene |
| Volume |
36 |
Issue |
17 |
Pages |
2423-2434 |
| Keywords |
Animals; Apoptosis/*drug effects; Cell Differentiation/*drug effects; Cell Line, Tumor; Cell Survival/drug effects; Cell Transformation, Neoplastic; Disease Progression; Enzyme Inhibitors/*pharmacology; Gene Expression Regulation, Neoplastic/drug effects; Glioma/*pathology; Histone Demethylases/*antagonists & inhibitors; Mice; Neoplastic Stem Cells/*drug effects/metabolism/pathology; Signal Transduction/drug effects; Survival Analysis; Transcription, Genetic/drug effects; Unfolded Protein Response/*drug effects |
| Abstract |
Glioma stem cells (GSCs) have a central role in glioblastoma (GBM) development and chemo/radiation resistance, and their elimination is critical for the development of efficient therapeutic strategies. Recently, we showed that lysine demethylase KDM1A is overexpressed in GBM. In the present study, we determined whether KDM1A modulates GSCs stemness and differentiation and tested the utility of two novel KDM1A-specific inhibitors (NCL-1 and NCD-38) to promote differentiation and apoptosis of GSCs. The efficacy of KDM1A targeting drugs was tested on purified GSCs isolated from established and patient-derived GBMs using both in vitro assays and in vivo orthotopic preclinical models. Our results suggested that KDM1A is highly expressed in GSCs and knockdown of KDM1A using shRNA-reduced GSCs stemness and induced the differentiation. Pharmacological inhibition of KDM1A using NCL-1 and NCD-38 significantly reduced the cell viability, neurosphere formation and induced apoptosis of GSCs with little effect on differentiated cells. In preclinical studies using orthotopic models, NCL-1 and NCD-38 significantly reduced GSCs-driven tumor progression and improved mice survival. RNA-sequencing analysis showed that KDM1A inhibitors modulate several pathways related to stemness, differentiation and apoptosis. Mechanistic studies showed that KDM1A inhibitors induce activation of the unfolded protein response (UPR) pathway. These results strongly suggest that selective targeting of KDM1A using NCL-1 and NCD-38 is a promising therapeutic strategy for elimination of GSCs. |
| Address |
Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA |
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English |
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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 |
0950-9232 |
ISBN |
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| Notes |
PMID:27893719 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96621 |
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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 |
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Edition |
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| ISSN |
0967-5868 |
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| Notes |
PMID:27865821 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96622 |
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| Author |
Jin, W.-L.; Mao, X.-Y.; Qiu, G.-Z. |
| Title |
Targeting Deubiquitinating Enzymes in Glioblastoma Multiforme: Expectations and Challenges |
Type |
Journal Article |
| Year |
2017 |
Publication |
Medicinal Research Reviews |
Abbreviated Journal |
Med Res Rev |
| Volume |
37 |
Issue |
3 |
Pages |
627-661 |
| Keywords |
Animals; Carcinogenesis/pathology; Deubiquitinating Enzymes/antagonists & inhibitors/*metabolism; Enzyme Inhibitors/pharmacology; Glioblastoma/*enzymology/*therapy; Humans; *Molecular Targeted Therapy; Neoplastic Stem Cells/drug effects/pathology; DUB inhibitor; DUBs; glioblastoma; glioma stem cells; proteasome |
| Abstract |
Glioblastoma (GBM) is regarded as the most common primary intracranial neoplasm. Despite standard treatment with tumor resection and radiochemotherapy, the outcome remains gloomy. It is evident that a combination of oncogenic gain of function and tumor-suppressive loss of function has been attributed to glioma initiation and progression. The ubiquitin-proteasome system is a well-orchestrated system that controls the fate of most proteins by striking a dynamic balance between ubiquitination and deubiquitination of substrates, having a profound influence on the modulation of oncoproteins, tumor suppressors, and cellular signaling pathways. In recent years, deubiquitinating enzymes (DUBs) have emerged as potential anti-cancer targets due to their targeting several key proteins involved in the regulation of tumorigenesis, apoptosis, senescence, and autophagy. This review attempts to summarize recent studies of GBM-associated DUBs, their roles in various cellular processes, and discuss the relation between DUBs deregulation and gliomagenesis, especially how DUBs regulate glioma stem cells pluripotency, microenvironment, and resistance of radiation and chemotherapy through core stem-cell transcriptional factors. We also review recent achievements and progress in the development of potent and selective reversible inhibitors of DUBs, and attempted to find a potential GBM treatment by DUBs intervention. |
| Address |
Department of Neurosurgery, General Hospital of Jinan Military Command, Jinan, 250031, P. R. China |
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English |
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Edition |
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0198-6325 |
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| Notes |
PMID:27775833 |
Approved |
no |
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ref @ user @ |
Serial |
96629 |
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| Author |
Nourallah, B.; Digpal, R.; Jena, R.; Watts, C. |
| Title |
Irradiating the Subventricular Zone in Glioblastoma Patients: Is there a Case for a Clinical Trial? |
Type |
Journal Article |
| Year |
2017 |
Publication |
Clinical Oncology (Royal College of Radiologists (Great Britain)) |
Abbreviated Journal |
Clin Oncol (R Coll Radiol) |
| Volume |
29 |
Issue |
1 |
Pages |
26-33 |
| Keywords |
Adult; Brain Neoplasms/*radiotherapy; Glioblastoma/*radiotherapy; Humans; Lateral Ventricles/*radiation effects; Male; Neoplastic Stem Cells/radiation effects; Stem Cell Niche/radiation effects; Cancer stem cells; glioblastoma; neural stem cells; radiotherapy; subventricular zone |
| Abstract |
Glioblastoma is the most common and aggressive adult brain tumour. Over the last 10 years it has emerged that the subventricular zone (SVZ), the largest adult neural stem cell niche, has an important role in the disease. Converging evidence has implicated transformation of adult neural stems in gliomagenesis and the permissive stem cell niche in disease recurrence. Concurrently, clinical studies have suggested that SVZ involvement is a negative prognostic marker. It would follow that irradiating the SVZ may improve outcomes in glioblastoma by directly targeting this putative sanctuary site. To investigate this potential strategy, 11 retrospective studies and 1 prospective study examined the relationship between dose to the SVZ and survival outcomes in glioblastoma patients. This review summarises the theoretical underpinning of this strategy, provides a critical evaluation of the existing evidence and discusses the rationale for a clinical trial. |
| Address |
John van Geest Centre for Repair, Cambridge, UK; Department of Clinical Neurosciences, Division of Neurosurgery, Addenbrookes Hospital, Cambridge, UK. Electronic address: cw209@cam.ac.uk |
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English |
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Edition |
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0936-6555 |
ISBN |
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| Notes |
PMID:27729188 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96633 |
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Luedi, M.M.; Singh, S.K.; Mosley, J.C.; Hatami, M.; Gumin, J.; Sulman, E.P.; Lang, F.F.; Stueber, F.; Zinn, P.O.; Colen, R.R. |
| Title |
A Dexamethasone-regulated Gene Signature Is Prognostic for Poor Survival in Glioblastoma Patients |
Type |
Journal Article |
| Year |
2017 |
Publication |
Journal of Neurosurgical Anesthesiology |
Abbreviated Journal |
J Neurosurg Anesthesiol |
| Volume |
29 |
Issue |
1 |
Pages |
46-58 |
| Keywords |
Animals; Antineoplastic Agents, Hormonal/*pharmacology; Apoptosis; Blotting, Western; Brain Neoplasms/*mortality; Cell Line, Tumor; Cell Survival; Dexamethasone/*pharmacology; Flow Cytometry; Gene Expression Regulation, Neoplastic/*drug effects; Glioblastoma/*mortality; Humans; Mice; Prognosis; Stem Cells/drug effects; Survival Analysis |
| Abstract |
BACKGROUND: Dexamethasone is reported to induce both tumor-suppressive and tumor-promoting effects. The purpose of this study was to identify the genomic impact of dexamethasone in glioblastoma stem cell (GSC) lines and its prognostic value; furthermore, to identify drugs that can counter these side effects of dexamethasone exposure. METHODS: We utilized 3 independent GSC lines with tumorigenic potential for this study. Whole-genome expression profiling and pathway analyses were done with dexamethasone-exposed and control cells. GSCs were also co-exposed to dexamethasone and temozolomide. Risk scores were calculated for most affected genes, and their associations with survival in The Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data databases. In silico Connectivity Map analysis identified camptothecin as antagonist to dexamethasone-induced negative effects. RESULTS: Pathway analyses predicted an activation of dexamethasone network (z-score: 2.908). Top activated canonical pathways included “role of breast cancer 1 in DNA damage response” (P=1.07E-04). GSCs were protected against temozolomide-induced apoptosis when coincubated with dexamethasone. Altered cellular functions included cell movement, cell survival, and apoptosis with z-scores of 2.815, 5.137, and -3.122, respectively. CCAAT/enhancer binding protein beta (CEBPB) was activated in a dose dependent manner specifically in slow-dividing “stem-like” cells. CEBPB was activated in dexamethasone-treated orthotopic tumors. Patients with high risk scores had significantly shorter survival. Camptothecin was validated as potential partial neutralizer of dexamethasone-induced oncogenic effects. CONCLUSIONS: Dexamethasone exposure induces a genetic program and CEBPB expression in GSCs that adversely affects key cellular functions and response to therapeutics. High risk scores associated with these genes have negative prognostic value in patients. Our findings further suggest camptothecin as a potential neutralizer of adverse dexamethasone-mediated effects. |
| Address |
*Department of Anesthesiology, Bern University Hospital Inselspital, Bern, Switzerland Departments of daggerCancer Systems Imaging double daggerDiagnostic Imaging section signNeurosurgery and Brain Tumor Center parallelRadiation Oncology, Division of Radiation Oncology #Neurosurgery, Cancer Systems Imaging, and Cancer Biology **Cancer Systems Imaging, and Diagnostic Imaging, The University of Texas MD Anderson Cancer Center paragraph signDepartment of Neurosurgery, Baylor College of Medicine, Houston, TX |
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English |
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0898-4921 |
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| Notes |
PMID:27653222 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96635 |
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