scholarly journals GD2 CAR T cells against human glioblastoma

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Malvina Prapa ◽  
Chiara Chiavelli ◽  
Giulia Golinelli ◽  
Giulia Grisendi ◽  
Marco Bestagno ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Antigen Expression ◽  
Primary Brain Tumor ◽  
Dependent Manner ◽  
Glioblastoma Cells ◽  
Incurable Cancer ◽  
Human Glioblastoma ◽  
Primary Glioblastoma ◽  
Antitumor Potential ◽  
Car T

AbstractGlioblastoma is the most malignant primary brain tumor and is still in need of effective medical treatment. We isolated patient-derived glioblastoma cells showing high GD2 antigen expression representing a potential target for CAR T strategy. Data highlighted a robust GD2 CAR antitumor potential in 2D and 3D glioblastoma models associated with a significant and CAR T-restricted increase of selected cytokines. Interestingly, immunosuppressant TGF β1, expressed in all co-cultures, did not influence antitumor activity. The orthotopic NOD/SCID models using primary glioblastoma cells reproduced human histopathological features. Considering still-conflicting data on the delivery route for targeting brain tumors, we compared intracerebral versus intravenous CAR T injections. We report that the intracerebral route significantly increased the length of survival time in a dose-dependent manner, without any side effects. Collectively, the proposed anti-GD2 CAR can counteract human glioblastoma potentially opening a new therapeutic option for a still incurable cancer.

scholarly journals Rutaecarpine Inhibits U87 Glioblastoma Cell Migration by Activating the Aryl Hydrocarbon Receptor Signaling Pathway

2021 ◽  
Vol 14 ◽  
Author(s):  
Yiyun Liu ◽  
Yangsheng Chen ◽  
Ruihong Zhu ◽  
Li Xu ◽  
Heidi Qunhui Xie ◽  
...  
Keyword(s):  
Cell Migration ◽  
Aryl Hydrocarbon Receptor ◽  
Signaling Pathway ◽  
Dependent Manner ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Migration Ability ◽  
Human Glioblastoma ◽  
Aryl Hydrocarbon ◽  
Human Glioblastoma Cells

Glioblastoma is the most frequent and aggressive primary astrocytoma in adults. The high migration ability of the tumor cells is an important reason for the high recurrence rate and poor prognosis of glioblastoma. Recently, emerging evidence has shown that the migration ability of glioblastoma cells was inhibited upon the activation of aryl hydrocarbon receptor (AhR), suggesting potential anti-tumor effects of AhR agonists. Rutaecarpine is a natural compound with potential tumor therapeutic effects which can possibly bind to AhR. However, its effect on the migration of glioblastoma is unclear. Therefore, we aim to explore the effects of rutaecarpine on the migration of human glioblastoma cells U87 and the involvement of the AhR signaling pathway. The results showed that: (i) compared with other structural related alkaloids, like evodiamine and dehydroevodiamine, rutaecarpine was a more potent AhR activator, and has a stronger inhibitory effect on the glioblastoma cell migration; (ii) rutaecarpine decreased the migration ability of U87 cells in an AhR-dependent manner; (iii) AhR mediated the expression of a tumor suppressor interleukin 24 (IL24) induced by rutaecarpine, and AhR-IL24 axis was involved in the anti-migratory effects of rutaecarpine on the glioblastoma. Besides IL24, other candidates AhR downstream genes both associated with cancer and migration were proposed to participate in the migration regulation of rutaecarpine by RNA-Seq and bioinformatic analysis. These data indicate that rutaecarpine is a naturally-derived AhR agonist that could inhibit the migration of U87 human glioblastoma cells mostly via the AhR-IL24 axis.

Anticancer Potential and Mechanism of Action of Mango Ginger (Curcuma amada Roxb.) Supercritical CO2 Extract in Human Glioblastoma Cells

2014 ◽  
Vol 20 (2) ◽  
pp. 109-119 ◽  
Author(s):  
Cheppail Ramachandran ◽  
Ivonne V. Lollett ◽  
Enrique Escalon ◽  
Karl-Werner Quirin ◽  
Steven J. Melnick
Keyword(s):  
Cell Line ◽  
Mechanism Of Action ◽  
Dependent Manner ◽  
Glioblastoma Cell Line ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Embryonic Mouse ◽  
Human Glioblastoma ◽  
Mango Ginger ◽  
Curcuma Amada

Mango ginger ( Curcuma amada Roxb.) is among the less-investigated species of Curcuma for anticancer properties. We have investigated the anticancer potential and the mechanism of action of a supercritical CO2 extract of mango ginger (CA) in the U-87MG human glioblastoma cell line. CA demonstrated higher cytotoxicity than temozolomide, etoposide, curcumin, and turmeric force with IC50, IC75, and IC90 values of 4.92 μg/mL, 12.87 μg/mL, and 21.30 μg/mL, respectively. Inhibitory concentration values of CA for normal embryonic mouse hypothalamus cell line (mHypoE-N1) is significantly higher than glioblastoma cell line, indicating the specificity of CA against brain tumor cells. CompuSyn analysis indicates that CA acts synergistically with temozolomide and etoposide for the cytotoxicity with combination index values of <1. CA treatment also induces apoptosis in glioblastoma cells in a dose-dependent manner and downregulates genes associated with apoptosis, cell proliferation, telomerase activity, oncogenesis, and drug resistance in glioblastoma cells.

scholarly journals IMMU-15. HEPARIN INHIBITS THE EXTRACELLULAR VESICLE-MEDIATED INDUCTION OF IMMUNOSUPPRESSIVE MONOCYTES IN GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii107-ii107
Author(s):  
Benjamin Himes ◽  
Cori Fain ◽  
Zachariah Tritz ◽  
Helen Li ◽  
Philipp Geiger ◽  
...  
Keyword(s):  
Standard Of Care ◽  
Extracellular Vesicle ◽  
Primary Brain Tumor ◽  
Immune Checkpoint Blockade ◽  
Target Cells ◽  
Initial Contact ◽  
Dependent Manner ◽  
Car T ◽  
Dose Dependent

Abstract Glioblastoma (GBM) is the most common and fatal primary brain tumor in adults. The development of novel therapies is critical, as little has changed regarding the standard of care in nearly two decades. Immunotherapy holds much promise, as treatments including chimeric antigen receptor (CAR) T cells and immune checkpoint blockade inhibitors have transformed the treatment of a number of cancers in recent years. However, GBM patients exhibit profound immunosuppression, limiting the efficacy of these therapies. Understanding the mechanisms of GBM-mediated immunosuppression is critical to overcoming this barrier. GBM-derived extracellular vesicles (EVs) have been shown to mediate the induction of immunosuppressive monocytes, which may point to a mechanism of immunosuppression. EVs make initial contact with target cells through interactions between heparan sulfate proteoglycans, and soluble heparin has been shown to inhibit these interactions in some models. We demonstrate that soluble heparin inhibits the binding of GBM-derived EVs to monocytes in a dose-dependent manner, and that heparin treatment reduces the induction of immunosuppressive monocytes upon in vitro conditioning of monocytes with GBM-derived EVs (p&lt; 0.01). Further, we demonstrate that heparin treated EV-conditioned monocytes are functionally less immunosuppressive than untreated EV-conditioned monocytes as measured by T cell proliferation in co-culture studies (p&lt; 0.05). Taken together, these findings underscore the import of tumor-derived EVs in immunosuppression in GBM, and demonstrate the feasibility of targeting EV-monocyte interactions in treating GBM-mediated immunosuppression.

Effect of recombinant tumor necrosis factor-α on three-dimensional growth, morphology, and invasiveness of human glioblastoma cells in vitro

1993 ◽  
Vol 78 (6) ◽  
pp. 952-958 ◽  
Author(s):  
Koichi Iwasaki ◽  
Lisa R. Rogers ◽  
Gene H. Barnett ◽  
Melinda L. Estes ◽  
Barbara P. Barna
Keyword(s):  
Tumor Necrosis ◽  
Three Dimensional ◽  
Dependent Manner ◽  
Glioblastoma Cells ◽  
Human Glioblastoma ◽  
Tnf Α ◽  
Human Glioblastoma Cells ◽  
Dose Dependent ◽  
Necrosis Factor

✓ In order to investigate the antiproliferative and anti-invasive effects of tumor necrosis factor (TNF)-α on human glioblastoma cells, an in vitro three-dimensional (anchorage-independent) assay was performed using Matrigel, a mixture of extracellular matrix proteins. Four glioblastoma-derived cell lines, including one cloned line, were cultured in Matrigel with or without TNF-α. In the Matrigel containing TNF-α, three of the four cell lines, including the cloned line, showed significant growth inhibition in a dose-dependent manner. Dramatic three-dimensional morphological differences were observed between TNF-treated and untreated glioblastoma cells cultured in Matrigel. Untreated cells formed large and highly branched colonies throughout the gel. In contrast, the majority of TNF-treated cells demonstrated truncated branching processes and, at a high TNF-α dose, an increasing number of cells remained in relatively small spherical aggregates, their cell processes being significantly reduced. Quantitative invasion assay using a micro-Boyden chamber system confirmed that TNF-treated cells lost invasiveness in a dose-dependent manner. These results suggest that TNF-α exerts not only antiproliferative but also anti-invasive effects on human glioblastoma cells in vitro. It is believed that this is the first report showing the anti-invasive effect of TNF-α on tumor cells.

scholarly journals DDRE-04. THE COMBINED TREATMENT OF L-ASPARAGINASE AND 6-DIAZO-5-OXO-L-NORLEUCINE INHIBIT THE PROLIFERATION OF TEMOZOLOMIDE-SENSITIVE OR RESISTANT GLIOBLASTOMA CELLS

2020 ◽  
Vol 3 (Supplement_1) ◽  
pp. i7-i7
Author(s):  
Shigeo Ohba ◽  
Yuichi Hirose
Keyword(s):  
Cancer Metabolism ◽  
Standard Treatment ◽  
Therapeutic Option ◽  
Combined Treatment ◽  
Recurrent Glioblastoma ◽  
Dependent Manner ◽  
Glioblastoma Cells ◽  
Single Drug ◽  
Dose Dependent ◽  
U87 Cells

Abstract Glioblastoma is one of the aggressive brain tumors with a 5-year survival rate of &lt; 10%. The standard treatment is maximal safe resection, followed by radiation therapy and temozolomide (TMZ). Clinically, the resistance to TMZ is a big problem. Cancer cells have been revealed to show different metabolism from normal cells. The object of this study is to evaluate whether cancer metabolism, especially asparagine, could be a new target of treatment in primary and recurrent glioblastoma. Glioblastoma cells (U251 and U87) were treated with L-asparaginase and/or 6-diazo-5-oxo-L-norleucine (DON). L-asparaginase converts asparagine into aspartate and depletes asparagine. DON is a glutamine analog that inhibits several glutamine-utilizing enzymes, including asparagine synthetase. L-asparaginase or DON suppressed the proliferation of U251, and U87 cells in a dose-dependent manner. Combined treatment with these drugs had a synergistic antiproliferative effect in these cell lines. The effect was counteracted by exogenous asparagine. The combined treatment induced greater apoptosis and autophagy than did single-drug treatment. Several clones of TMZ-resistant U251 were obtained after long treatment of TMZ to U251. The expression of MSH6, one of the mismatch repair proteins, was suppressed in these resistant clones. The synergistic effect of L-asparaginase and DON was detected in these U251-derived TMZ-resistant clones. These results suggest that the combination of L-asparaginase and DON could be a new therapeutic option for patients with primary and recurrent glioblastoma.

scholarly journals Protective Effect of Pyrus ussuriensis Maxim. Extract against Ethanol-Induced Gastritis in Rats

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 439
Author(s):  
Naila Boby ◽  
Muhammad Aleem Abbas ◽  
Eon-Bee Lee ◽  
Zi-Eum Im ◽  
Walter H. Hsu ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Adenosine Monophosphate ◽  
Ethanol Ingestion ◽  
Dependent Manner ◽  
Protective Effects ◽  
Gastric Mucosal Lesions ◽  
Cellular Degeneration ◽  
Mucosal Lesions ◽  
Pyrus Ussuriensis Maxim

Pyrus ussuriensis Maxim (Korean pear) has been used for hundreds of years as a traditional herbal medicine for asthma, cough, and atopic dermatitis in Korea and China. Although it was originally shown to possess anti-inflammatory, antioxidant, and antiatopic properties, its gastroprotective effects have not been investigated. In the present study, we evaluated the protective effects of Pyrus ussuriensis Maxim extract (PUE) against ethanol-induced gastritis in rats. The bioactive compound profile of PUE was determined by gas chromatography mass spectroscopy (GC-MS) and high-performance liquid chromatography (HPLC). The gastroprotection of PUE at different doses (250 and 500 mg/kg body weight) prior to ethanol ingestion was evaluated using an in vivo gastritis rat model. Several endpoints were evaluated, including gastric mucosal lesions, cellular degeneration, intracellular damage, and immunohistochemical localization of leucocyte common antigen. The gastric mucosal injury and ulcer score were determined by evaluating the inflamed gastric mucosa and by histological examination. To identify the mechanisms of gastroprotection by PUE, antisecretory action and plasma prostaglandin E2 (PGE2), gastric mucosal cyclic adenosine monophosphate (cAMP), and histamine levels were measured. PUE exhibited significant antioxidant effects with IC50 values of 56.18 and 22.49 µg/mL for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′- azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) inhibition (%), respectively. In addition, GC/MS and HPLC analyses revealed several bioactive compounds of PUE. Pretreatment with PUE significantly (P < 0.05) decreased the ulcer index by preventing gastric mucosal lesions, erosion, and cellular degeneration. An immunohistochemical analysis revealed that PUE markedly attenuated leucocyte infiltration in a dose-dependent manner. The enhancement of PGE2 levels and attenuation of cAMP levels along with the inhibition of histamine release following PUE pretreatment was associated with the cytoprotective and healing effects of PUE. In contrast, the downregulation of the H+/K+ ATPase pathway as well as muscarinic receptor (M3R) and histamine receptor (H2R) inhibition was also involved in the gastroprotective effects of PUE; however, the expression of cholecystokinin-2 receptors (CCK2R) was unchanged. Finally, no signs of toxicity were observed following PUE treatment. Based on our results, we conclude that PUE represents an effective therapeutic option to reduce the risk of gastritis and warrants further study.

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