In Search of a Breakthrough Therapy for Glioblastoma Multiforme

Vasilev, Alex; Sofi, Roba; Li, Tong; Teschemacher, Anja G.; Kasparov, Sergey

doi:10.3390/neuroglia1020020

Cited by 11 publications

(10 citation statements)

References 123 publications

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“…The recognized overrepresentation of the 5-hydroxytryptamine degredation pathway could be consistent with literature data [ 19 , 20 ]. Studies in vitro on glioma cell lines interestingly showed enhanced cell proliferation following serotonin (5-hydroxytryptamine, 5HT) administration, exhibiting an invasion-promoting effect [ 19 ].…”

Section: Discussionsupporting

confidence: 92%

“…Studies in vitro on glioma cell lines interestingly showed enhanced cell proliferation following serotonin (5-hydroxytryptamine, 5HT) administration, exhibiting an invasion-promoting effect [ 19 ]. The administration of 5-HT receptor agonists resulted in a high inhibition of glioma stem cell proliferation and very recently serotonin receptors inhibitor drugs have been listed among the candidates for GBM therapies [ 20 ]. A review by Plun-Favreau et al [ 21 ] discusses the various gene mutations that were found to be present and possibly link various neurodegenerative diseases, such as Huntington’s, with CNS tumors.…”

Section: Discussionmentioning

confidence: 99%

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Glioblastoma CUSA Fluid Protein Profiling: A Comparative Investigation of the Core and Peripheral Tumor Zones

Rocca¹,

Simboli

Vincenzoni

et al. 2020

Cancers

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The present investigation aimed to characterize the protein profile of cavitating ultrasound aspirator fluid of newly diagnosed and recurrent glioblastoma comparing diverse zones of collection, i.e., tumor core and tumor periphery, with the aid of 5-aminolevulinic acid fluorescence. The samples were pooled and analyzed in triplicate by LC-MS following the shotgun proteomic approach. The identified proteins were then grouped to disclose elements exclusive and common to the tumor state or tumor zones and submitted to gene ontology classification and pathway overrepresentation analysis. The proteins common to the distinct zones were further investigated by relative quantitation, following a label free approach, to disclose possible differences of expression. Nine proteins, i.e., tubulin 2B chain, CD59, far upstream element-binding, CD44, histone H1.4, caldesmon, osteopontin, tropomyosin chain and metallothionein-2, marked the core of newly diagnosed glioblastoma with respect to tumor periphery. Considering the tumor zone, including the core and the fluorescence positive periphery, the serine glycine biosynthesis, pentose phosphate, 5-hydroxytryptamine degredation, de novo purine biosynthesis and huntington disease pathways resulted statistically significantly overrepresented with respect to the human genome of reference. The fluorescence negative zone shared several protein elements with the tumor zone, possibly indicating the presence of pathological aspects of glioblastoma rather than of normal brain parenchyma. On the other hand, its exclusive protein elements were considered to represent the healthy zone and, accordingly, exhibiting no pathways overrepresentation. On the contrary to newly diagnosed glioblastoma, pathway overrepresentation was recognized only in the healthy zone of recurrent glioblastoma. The TGFβ signaling pathway, exclusively classified in the fluorescence negative periphery in newly diagnosed glioblastoma, was instead the exclusive pathway classified in the tumor core of recurrent glioblastoma. These results, preliminary obtained on sample pools, demonstrated the potential of cavitron ultrasonic surgical aspirate fluid for proteomic profiling of glioblastoma able to distinguish molecular features specific of the diverse tumor zones and tumor states, possibly contributing to the understanding of the highly infiltrative capability and recurrent rate of this aggressive brain tumor and opening to potential clinical applications to be further investigated.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Glioblastoma CUSA Fluid Protein Profiling: A Comparative Investigation of the Core and Peripheral Tumor Zones

Rocca¹,

Simboli

Vincenzoni

et al. 2020

Cancers

View full text Add to dashboard Cite

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“…By blocking the synthesis of mevalonate, a rate limiting step of the biosynthesis of cholesterol, they have also demonstrated potential cytotoxic activity over several cancer types, including glioblastoma. Similarly to CUR, ATO also possesses a lipophilic behavior, low solubility and low oral bioavailability (Vasilev et al, 2018;Jones et al, 2017;Prabhu and Patravale, 2016).…”

Section: Introductionmentioning

confidence: 99%

Biomimeting ultra-small lipid nanoconstructs for glioblastoma treatment: A computationally guided experimental approach

Mendes¹,

Silva²,

Cova

et al. 2020

International Journal of Pharmaceutics

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Ultra-small nanostructured lipid carriers (usNLCs) are stable, biocompatible and biodegradable colloidal systems, claiming a broad set of advanced features suitable for cancer drug delivery. To unleash their potential in glioblastoma research and therapy, we have developed an usNLC prototype able to co-encapsulate atorvastatin calcium and curcumin, as repurposed drugs previously screened from molecular dynamics simulations. The novelty not only relies on the drug repositioning approach, but also on a robust computational methodology utilized for formulation optimization, under the umbrella of multivariate analysis and full factorial designs. A coating procedure with red blood cell membranes is ultimately hypothesized, aiming at integrating the biomimetic concept into usNLCs for glioblastoma therapeutics. The formulation composition and process parameters, that demonstrated a high-risk level for the final quality and performance of the usNLCs, include the solid:liquid lipid ratio, type and concentration of liquid lipids and surfactants, along with the type of production method. Particles with an average diameter of ca. 50 nm, and a polydispersity index lower than 0.3 were produced, exhibiting high stability, up-scalability, drug protection and sustained co-release properties, meeting the suitable critical quality attributes for intravenous administration. Also, a Taguchi design was successfully applied to optimizing usNLCs as cell membrane-coating technology.

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“…Dozens of drugs have been reported to have anti-GBM properties in vitro but there is no solid evidence for the clinical efficacy of any of them (Vasilev et al, 2018). Effective therapies for GBM are lacking and hardly any progress in its treatment has been made in the last 15 years.…”

Section: T19-009bmentioning

confidence: 99%

GLIA Porto 2019: Abstracts Oral Presentations, Posters, Indexes

2019

Glia

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Reversible oxidative modifications regulate protein activity. Oxidoreductases such as Glutaredoxin 2 control the thiol redox state of proteins. Here, we demonstrate that Glutaredoxin 2 modifies the cytoskeleton and thereby migration capacity of glia cells. The lack of Glutaredoxin 2 decreases transmigration of mouse primary oligodendrocyte progenitor cells, whereas enhanced levels of Glutaredoxin 2 increase migration. In both, transmigration and scratch closure Glutaredoxin 2 is able to overcome the inhibitory effect of Semaphorin 3A. We found that Glutaredoxin 2 levels control expression of NG2. Therefore, enhanced levels of Glutaredoxin 2 not only affect migration, but also block differentiation of oligodendrocytes in the NG2-glia state. The importance of Glutaredoxin 2 during migration and differentiation of progenitor cells was confirmed in zebrafish with manipulated Glutaredoxin 2 translation. Since NG2/CSPG4 is associated with metastasis/invasion of cancer cells, we investigated the impact of Glutaredoxin 2 on migration and invasion of glioblastoma cells. Injection of patient derived glioblastoma cells with or without manipulated expression of Glutaredoxin 2 into developing zebrafish embryos revealed that Glutaredoxin 2 is essential for metastasis/invasion of glioblastoma cells. Via the migration of glia cells, our data connect specific redox regulation with physiological and pathological processes during development of the myelin sheeth, tissue regeneration, and glioblastoma invasion. E128 POSTERS GLIA Different types of brain damage induce activation and migration of microglial cells towards injury sites. Deregulated microglial response contributes to the development and propagation of various neurological disorders and therefore targeting of neuroinflammatory microglia is considered as a novel therapeutic strategy. We investigated effects of extracellular vesicles (EVs) derived from human dental pulp stem cells (DPSCs) and recently suggested as promising regenerative tools in neurological disorders, on ATP signalling in human microglial cells. Human immortalized (SV40) microglial cells were cultivated in exosome-depleted medium. EVs were purified by differential ultracentrifugation from DPSCs grown in serum-and xeno-free medium. Migration assays have been performed in Boyden chamber using 8 μm pore membranes. Changes in the intracellular Ca2+ concentration in single cells loaded with Fluo-4 AM were monitored with Till Photonic imaging system. Extracellular ATP concentrations were measured by ATPlite Luminescence Assay System. We found that EVs induced a rapid increase of intracellular Ca2+ in microglial cells and promoted a significant ATP release (by 123 % and 68 % after 20 and 60 min, respectively). EVs increased migration of microglial cells by 20 % whereas ATP degrading enzyme apyrase (20 U/ml) reduced migration by 23%. In apyrase-treated cells, EVs increased migration more efficiently (by 36 %). The nonselective antagonist of ATP-gated P2 receptors suramin (200 µM) decreased cell migration by 21 %. ...

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In Search of a Breakthrough Therapy for Glioblastoma Multiforme

Cited by 11 publications

References 123 publications

Glioblastoma CUSA Fluid Protein Profiling: A Comparative Investigation of the Core and Peripheral Tumor Zones

Glioblastoma CUSA Fluid Protein Profiling: A Comparative Investigation of the Core and Peripheral Tumor Zones

Biomimeting ultra-small lipid nanoconstructs for glioblastoma treatment: A computationally guided experimental approach

GLIA Porto 2019: Abstracts Oral Presentations, Posters, Indexes

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