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Mirella Baroni, Suely Kazue Nagahashi Marie, Paola Fernanda Fedatto, Augusto Faria Andrade, Veridiana Kill Suazo, Gustavo Alencastro Veiga Cruzeiro, Rosane de Paula Queiroz, Luiz Gonzaga Tone, Carlos Alberto Scrideli
INTRODUCTION: Glioblastoma (GBM) is the most common malignant primary brain tumor affecting adults. In pediatric patients, GBM exhibits genetic variations distinct from those identified in the adult GBM phenotype. This tumor exhibits complex genetic changes leading to malignant progression and resistance to standard therapies including radiotherapy and temozolomide treatment. The GDF15 gene codes for a growth factor whose expression is altered in the presence of inflammations and malignancies...
April 18, 2018: Journal of Neuro-oncology
Giuseppina Catanzaro, Claudia Sabato, Michele Russo, Alessandro Rosa, Luana Abballe, Zein Mersini Besharat, Agnese Po, Evelina Miele, Diana Bellavia, Martina Chiacchiarini, Marco Gessi, Giovanna Peruzzi, Maddalena Napolitano, Manila Antonelli, Angela Mastronuzzi, Felice Giangaspero, Franco Locatelli, Isabella Screpanti, Alessandra Vacca, Elisabetta Ferretti
The mechanisms by which microRNAs control pediatric high-grade gliomas (pHGGs) have yet to be fully elucidated. Our studies of patient-derived pHGG tissues and of the pHGG cell line KNS42 revealed down-regulation in these tumors of three microRNAs, specifically miR-107, miR-181c, and miR-29a-3p. This down-regulation increases the proliferation of KNS42 cells by de-repressing expression of the Notch2 receptor (Notch2), a validated target of miR-107 and miR-181c and a putative target of miR-29a-3p. Inhibition (either pharmacologic or genetic) of Notch2 or re-expression of the implicated microRNAs (all three combined but also individually) significantly reduced KNS42 cell proliferation...
December 17, 2017: International Journal of Molecular Sciences
Nada M S Al-Saffar, Alice Agliano, Lynley V Marshall, L Elizabeth Jackson, Geetha Balarajah, Jasmin Sidhu, Paul A Clarke, Chris Jones, Paul Workman, Andrew D J Pearson, Martin O Leach
Recent experimental data showed that the PI3K pathway contributes to resistance to temozolomide (TMZ) in paediatric glioblastoma and that this effect is reversed by combination treatment of TMZ with a PI3K inhibitor. Our aim is to assess whether this combination results in metabolic changes that are detectable by nuclear magnetic resonance (NMR) spectroscopy, potentially providing metabolic biomarkers for PI3K inhibition and TMZ combination treatment. Using two genetically distinct paediatric glioblastoma cell lines, SF188 and KNS42, in vitro 1H-NMR analysis following treatment with the dual pan-Class I PI3K/mTOR inhibitor PI-103 resulted in a decrease in lactate and phosphocholine (PC) levels (P<0...
2017: PloS One
Heather Marion Ames, Ming Yuan, Maria Adelita Vizcaíno, Wayne Yu, Fausto J Rodriguez
Low-grade (WHO I-II) gliomas and glioneuronal tumors represent the most frequent primary tumors of the central nervous system in children. They often have a good prognosis following total resection, however they can create many neurological complications due to mass effect, and may be difficult to resect depending on anatomic location. MicroRNAs have been identified as molecular regulators of protein expression/translation that can repress multiple mRNAs concurrently through base pairing, and have an important role in cancer, including brain tumors...
February 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
Pamela Viani de Andrade, Augusto Faria Andrade, Rosane Gomes de Paula Queiroz, Carlos Alberto Scrideli, Luiz Gonzaga Tone, Elvis Terci Valera
BACKGROUND: Glioblastoma (GBM) is considered to be one of the most aggressive tumors of the central nervous system (CNS). Even with the use of modern treatment protocols, the prognosis remains reserved, with children with GBM having a mean survival of 12-15 months. METHODS: In the present study we investigated the potential radiosensitizing effect of PCI-24781, a potent pan-histone deacetylase inhibitor (HDACi), on the SF188 and KNS42 cell lines of pediatric GBM...
2016: Cancer Cell International
J V Cockle, S Picton, J Levesley, E Ilett, A M Carcaboso, S Short, L P Steel, A Melcher, S E Lawler, A Brüning-Richardson
BACKGROUND: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed. METHODS: Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays...
February 17, 2015: British Journal of Cancer
Nada M S Al-Saffar, Lynley V Marshall, L Elizabeth Jackson, Geetha Balarajah, Thomas R Eykyn, Alice Agliano, Paul A Clarke, Chris Jones, Paul Workman, Andrew D J Pearson, Martin O Leach
The phosphoinositide 3-kinase (PI3K) pathway is believed to be of key importance in pediatric glioblastoma. Novel inhibitors of the PI3K pathway are being developed and are entering clinical trials. Our aim is to identify potential non-invasive biomarkers of PI3K signaling pathway inhibition in pediatric glioblastoma using in vitro nuclear magnetic resonance (NMR) spectroscopy, to aid identification of target inhibition and therapeutic response in early phase clinical trials of PI3K inhibitors in childhood cancer...
2014: PloS One
Jae Kyung Myung, Seung Ah Choi, Seung-Ki Kim, Kyu-Chang Wang, Sung-Hye Park
BACKGROUND: The factors affecting glioblastoma progression are of great clinical importance since dismal outcomes have been observed for glioblastoma patients. The Snail gene is known to coordinate the regulation of tumor progression in diverse tumors through induction of epithelial mesenchymal transition (EMT); however, its role in glioblastoma is still uncertain. Therefore, we aimed to further define its role in vitro. METHODS AND RESULTS: The small interfering RNA (siRNA) technique was employed to knock down Snail expression in three glioblastoma cell lines (KNS42, U87, and U373)...
2014: International Journal of Clinical and Experimental Pathology
Sunil Lagah, I-Li Tan, Priya Radhakrishnan, Robert A Hirst, Jennifer H Ward, Chris O'Callaghan, Stuart J Smith, Malcolm F G Stevens, Richard G Grundy, Ruman Rahman
BACKGROUND: Telomeric 3' overhangs can fold into a four-stranded DNA structure termed G-quadruplex (G4), a formation which inhibits telomerase. As telomerase activation is crucial for telomere maintenance in most cancer cells, several classes of G4 ligands have been designed to directly disrupt telomeric structure. METHODS: We exposed brain tumor cells to the G4 ligand 3,11-difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate (RHPS4) and investigated proliferation, cell cycle dynamics, telomere length, telomerase activity and activated c-Myc levels...
2014: PloS One
Jane Levesley, Lynette Steele, Claire Taylor, Priyank Sinha, Sean E Lawler
Pediatric high grade glioma is refractory to conventional multimodal treatment, highlighting a need to develop novel efficacious therapies. We investigated tumor metabolism as a potential therapeutic target in a panel of diverse pediatric glioma cell lines (SF188, KNS42, UW479 and RES186) using metformin and 2-deoxyglucose. As a single agent, metformin had little effect on cell viability overall. SF188 cells were highly sensitive to 2-deoxyglucose however, combination of metformin with 2-deoxyglucose significantly reduced cell proliferation compared to either drug alone in all cell lines tested...
2013: PloS One
Stuart J Smith, Martin Wilson, Jennifer H Ward, Cheryl V Rahman, Andrew C Peet, Donald C Macarthur, Felicity R A J Rose, Richard G Grundy, Ruman Rahman
INTRODUCTION: Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS). METHODS: CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat...
2012: PloS One
Minori Kamada, Keiichi Ikeda, Kouki Fujioka, Noibutake Akiyama, Kouhei Akiyoshi, Yuriko Inoue, Sanshiro Hanada, Kenji Yamamoto, Katsuyoshi Tojo, Yoshinobu Manome
BACKGROUND: Urocortin and corticotropin-releasing factors (CRFs) and their receptors are expressed in many organs, including the central nervous system. In this study, the expression of mRNAs of urocortin 1, 2, 3, and CRF and CRF receptors 1 and 2 in malignant glioma, was examined. MATERIALS AND METHODS: The RNAs of human and rat glioma cell lines were isolated. Transcripts in these cells were analyzed using cDNA. In addition, the effects of proliferative and cytotoxic stimulation by serum supplementation, ionizing radiation, and the antineoplastic agent temozolomide were investigated...
December 2012: Anticancer Research
Nobuharu Inaba, Kouki Fujioka, Hidetsugu Saito, Masaki Kimura, Keiichi Ikeda, Yuriko Inoue, Sho Ishizawa, Yoshinobu Manome
BACKGROUND: Malignant glioma is an invasive disease of the central nervous system. One of the factors that regulate growth of these tumors is expression of epidermal growth factor receptor (EGFR) in the cells. This study investigated the effects of down-regulation of EGFR on cell proliferation, cell cycle and cytotoxicity to antineoplastic agent. MATERIALS AND METHODS: A short hairpin RNA transcription vector targeting EGFR was transfected into KNS42 cells. Growth curve, cell cycle and sensitivity to temozolomide of the cells were assessed...
October 2011: Anticancer Research
Aleksandra Bielen, Lara Perryman, Gary M Box, Melanie Valenti, Alexis de Haven Brandon, Vanessa Martins, Alexa Jury, Sergey Popov, Sharon Gowan, Sebastien Jeay, Florence I Raynaud, Francesco Hofmann, Darren Hargrave, Suzanne A Eccles, Chris Jones
Pediatric glioblastoma (pGBM), although rare, is one of the leading causes of cancer-related deaths in children, with tumors essentially refractory to existing treatments. We have identified IGF1R to be a potential therapeutic target in pGBM due to gene amplification and high levels of IGF2 expression in some tumor samples, as well as constitutive receptor activation in pGBM cell lines. To evaluate the therapeutic potential of strategies targeting the receptor, we have carried out in vitro and in vivo preclinical studies using the specific IGF1R inhibitor NVP-AEW541...
August 2011: Molecular Cancer Therapeutics
Nathalie Gaspar, Lynley Marshall, Lara Perryman, Dorine A Bax, Suzanne E Little, Marta Viana-Pereira, Swee Y Sharp, Gilles Vassal, Andrew D J Pearson, Rui M Reis, Darren Hargrave, Paul Workman, Chris Jones
Sensitivity to temozolomide is restricted to a subset of glioblastoma patients, with the major determinant of resistance being a lack of promoter methylation of the gene encoding the repair protein DNA methyltransferase MGMT, although other mechanisms are thought to be active. There are, however, limited preclinical data in model systems derived from pediatric glioma patients. We screened a series of cell lines for temozolomide efficacy in vitro, and investigated the differential mechanisms of resistance involved...
November 15, 2010: Cancer Research
Satoshi Takahashi, Hisafumi Yamada-Okabe, Kenji Hamada, Shigeki Ohta, Takeshi Kawase, Kazunari Yoshida, Masahiro Toda
To identify molecular therapeutic targets for glioma, we performed gene expression profiling by using a complementary DNA (cDNA) microarray method and identified the urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) as a gene expressed highly in glioma tissue compared with the normal brain tissue. The uPARAP is an endocytic receptor for collagen. In certain cell types, uPARAP occurs in a complex with the urokinase plasminogen activator receptor (uPAR) where it fulfills other functions in addition to collagenolysis...
June 2011: Journal of Neuro-oncology
Nathalie Gaspar, Swee Y Sharp, Suzanne A Eccles, Sharon Gowan, Sergey Popov, Chris Jones, Andrew Pearson, Gilles Vassal, Paul Workman
The dismal prognosis of glioblastoma (GB) indicates the urgent need for new therapies for these tumors. Heat shock protein 90 (HSP90) inhibitors induce the proteasome-mediated degradation of many oncogenic client proteins involved in all of the hallmark characteristics of cancer. Here, we explored the mechanistic potential of the potent synthetic diarylisoxazole amide resorcinol HSP90 inhibitor, NVP-AUY922, in adult and pediatric GB. In vitro antiproliferative potency (nanomolar range) was seen in both adult and pediatric human GB cell lines with different molecular pathologies...
May 2010: Molecular Cancer Therapeutics
Yoshinobu Manome, Shuichi Mizuno, Nobutake Akiyama, Kouki Fujioka, Hideki Saito, Yoshiaki Hataba, Toshiaki Kobayashi, Michiko Watanabe
BACKGROUND: To explore the intracranial behaviors of glioma, a three-dimensional culture was devised and the morphology of four cell lines was examined. MATERIALS AND METHODS: Bioabsorbable and degradable gelatin was used as the scaffold and T98G, A172, KNS42, and U118MG representative standard malignant glioma cell lines were cultured three-dimensionally. RESULTS: When grown, the cells demonstrated characteristic conformations. The U118MG cells dispersed with numerous fiber formations...
February 2010: Anticancer Research
Hiromi Murakami, Hiroki Sawa, Hajime Kamada
Cyclooxygenase (COX)-2 of astrocytic tumors was studied by immunohistochemistry. COX-2 was expressed in 8 of 12 (75%) glioblastoma multiforme, 1 of 7 (14%) anaplastic astrocytoma, but none in astrocytoma. COX-2 was detected by an immnoblotting in 2 of 9 human glioblastoma cell lines (KNS42 and U138). In glioblastoma cell lines, NS398 and Etodolac inhibited cell proliferation and induced apoptosis. The result showed that COX-2 expression may be related with histological grades and COX-2 inhibitors will be one of promising therapeutic tools in human astrocytic tumors...
January 2006: Nō to Shinkei, Brain and Nerve
A Kawamura, N Tamaki, T Kokunai
The effect of glucocorticoid on cell proliferation, the expression of glucocorticoid receptor, and the relationship between inhibition of cell growth and apoptosis were investigated in four established neuroepithelial tumor cell lines (KNS42, T98G, A172, and U251MG). Glucocorticoid receptor expression was located in the cytoplasm of untreated cells, but translocated into nuclei after treatment with dexamethasone in KNS42, T98G, and A172 cells. U251MG did not express glucocorticoid receptors. Dexamethasone significantly inhibited the growth of KNS42 and T98G cell lines, at high concentrations in contrast to growth stimulation at low concentration...
October 1998: Neurologia Medico-chirurgica
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