A Novel Highly Selective Cannabinoid CB2 Agonist Reduces in vitro Growth and TGF-beta Release of Human Glial Cell Tumors

2019 ◽  
Vol 19 (3) ◽  
pp. 206-214 ◽  
Author(s):  
Chiara Cioni ◽  
Maristella Tassi ◽  
Giuseppe Marotta ◽  
Claudia Mugnaini ◽  
Federico Corelli ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Cell Cultures ◽  
Anaplastic Astrocytoma ◽  
Glioma Cell ◽  
Receptor Expression ◽  
Cb2 Receptor ◽  
Tgf Beta ◽  
Human Gliomas ◽  
Cb2 Agonist

Background: Cannabinoid receptors have been detected in human gliomas and cannabinoids have been proposed as novel drug candidates in the treatment of brain tumors. Aims: To test the in vitro antitumor activity of COR167, a novel cannabinoid CB2-selective agonist displaying a high binding affinity for human CB2 receptors, on tumor cells isolated from human glioblastoma multiforme and anaplastic astrocytoma. Methods: Glioma cell cultures were established from two glioblastoma multiforme and two anaplastic astrocytomas. Proliferation was measured in the presence or absence of COR167 with a bromodeoxyuridine (BrdU) cell proliferation ELISA assay. CB2 receptor expression was detected by western blotting. Apoptosis was assessed with phycoerythrin (PE) annexin V flow cytometry kit. TGF-beta 1 and 2 levels were analyzed in culture supernatants with commercial ELISAs. Results: COR167 was found to significantly reduce the proliferation of both glioblastoma and anaplastic astrocytoma in a dose-dependent manner at lower doses than other known, less specific CB2 agonists. This activity is independent of apoptosis and is associated with a significant reduction of TGF-beta 1 and 2 levels in supernatants of glioma cell cultures. Conclusion: These findings add to the role of cannabinoid CB2 receptor as a possible pharmacological target to counteract glial tumor growth and encourage further work to explore any other pharmacological effect of this novel CB2 agonist useful in the treatment of human gliomas.

P13.23 Study of migration characteristics of human glioma cells in vitro

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii37-ii38
Author(s):  
G Pavlova ◽  
S Pavlova ◽  
S Drozd ◽  
E Savchenko ◽  
L Zakharova ◽  
...  
Keyword(s):  
Cell Cultures ◽  
Proliferative Activity ◽  
Average Rate ◽  
Glioma Cells ◽  
Human Glioma ◽  
Human Gliomas ◽  
Migration Activity ◽  
Tumor Invasiveness ◽  
Grade Iii

Abstract BACKGROUND Gliomas are still one of the most aggressive human cancers, and even despite modern therapeutic approaches, the prognosis for patients with this disease is not favorable. It is known that glioma cells are capable of local invasiveness, when glioma cells migrate into healthy brain tissue. A lack of any definite markers, characterizing migrating glioma cells and allowing them to be distinguished from healthy brain cells, requires a thorough investigation. In case it would be possible to characterize invasive glioma cells, then a development of targeted therapy could be feasible. MATERIAL AND METHODS Cell cultures of human gliomas Gr II, III and IV were developed with 5 cultures for each Grade. MTT, RT-PCR, Western and Nosern blot, transcriptome analysis were applied. RESULTS Three cultures of human gliomas had a high degree of migration, within the range of 6% - 14%. These cultures were developed from gliomas of Grade III and Grade IV, and with IDH1- (minus) phenotype. Moreover, cell cultures with IDH1 + (plus) phenotype had a low migration rate within 1%. An intensity of migration correlated with the degree of malignancy, and an average rate decreased with a decrease of the Grade. Moreover, an analysis of the proliferative activity of cell cultures of human gliomas of various degrees of malignancy did not reveal a relationship with a migratory properties of cultures. A number of actively proliferating cultures did not show high migration, while cultures with medium proliferative activity could show a high level of migration. The low level of proliferation of cultures of gliomas of Grade II and I at the beginning of cultivation, in some cases, subsequently increased, but an inherent low migration activity did not change. In actively migrating cultures, a significant decrease in the expression of Sox2 and Nestin is detected. A positive correlation was found between migration abilities of human glioma cell culture cells and the marker Ki67, GFAP, Sox2, and Oct4. The difference was statistically significant by the one-sided Mann-Whitney test. CONCLUSION Conclusions: Cell cultures derived from glioma tumor tissue can be used to predict invasive properties of the tumor. High tumor invasiveness is characteristic for Grade III and Grade IV, and with IDH1- (minus) phenotype, and it also correlates with elevated expression of GFAP, Sox2 and Oct4The reported study was funded by RFBR according to the research project № 18-29-01012 and by the Ministry of Science and Higher Education of the Russian Federation, grant number 075-15-2020-809 (13.1902.21.0030).

Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas

2010 ◽  
Vol 56 (6-7) ◽  
pp. 829-833 ◽  
Author(s):  
Maider López De Jesús ◽  
Cristina Hostalot ◽  
Jesús M. Garibi ◽  
Joan Sallés ◽  
J. Javier Meana ◽  
...  
Keyword(s):  
Receptor Expression ◽  
Cb2 Receptor ◽  
Human Gliomas

scholarly journals PET imaging of cannabinoid type 2 receptors with [11C]A-836339 did not evidence changes following neuroinflammation in rats

2017 ◽  
Vol 37 (3) ◽  
pp. 1163-1178 ◽  
Author(s):  
Geraldine Pottier ◽  
Vanessa Gómez-Vallejo ◽  
Daniel Padro ◽  
Raphaël Boisgard ◽  
Frédéric Dollé ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Pet Imaging ◽  
Receptor Expression ◽  
Brain Inflammation ◽  
Cb2 Receptor ◽  
Future Studies ◽  
Positron Emission

Cannabinoid type 2 receptors (CB2R) have emerged as promising targets for the diagnosis and therapy of brain pathologies. However, no suitable radiotracers for accurate CB2R mapping have been found to date, limiting the investigation of the CB2 receptor expression using positron emission tomography (PET) imaging. In this work, we report the evaluation of the in vivo expression of CB2R with [11C]A-836339 PET after cerebral ischemia and in two rat models of neuroinflammation, first by intrastriatal LPS and then by AMPA injection. PET images and in vitro autoradiography showed a lack of specific [11C]A-836339 uptake in these animal models demonstrating the limitation of this radiotracer to image CB2 receptor under neuroinflammatory conditions. Further, using immunohistochemistry, the CB2 receptor displayed a modest expression increase after cerebral ischemia, LPS and AMPA models. Finally, [18F]DPA-714-PET and immunohistochemistry demonstrated decreased neuroinflammation by a selective CB2R agonist, JWH133. Taken together, these findings suggest that [11C]A-836339 is not a suitable radiotracer to monitor in vivo CB2R expression by using PET imaging. Future studies will have to investigate alternative radiotracers that could provide an accurate binding to CB2 receptors following brain inflammation.

scholarly journals Vitamin E-Mediated Modulation of Glutamate Receptor Expression in an Oxidative Stress Model of Neural Cells Derived from Embryonic Stem Cell Cultures

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Afifah Abd Jalil ◽  
Huzwah Khaza’ai ◽  
Norshariza Nordin ◽  
Nur’izzati Mansor ◽  
Amirah Salwani Zaulkffali
Keyword(s):  
Oxidative Stress ◽  
Vitamin E ◽  
Glutamate Receptor ◽  
Cell Cultures ◽  
Embryonic Stem ◽  
Receptor Expression ◽  
Neural Cells ◽  
Es Cell ◽  
Neural Lineage

Glutamate is the primary excitatory neurotransmitter in the central nervous system. Excessive concentrations of glutamate in the brain can be excitotoxic and cause oxidative stress, which is associated with Alzheimer’s disease. In the present study, the effects of vitamin E in the form of tocotrienol-rich fraction (TRF) and alpha-tocopherol (α-TCP) in modulating the glutamate receptor and neuron injury markers in an in vitro model of oxidative stress in neural-derived embryonic stem (ES) cell cultures were elucidated. A transgenic mouse ES cell line (46C) was differentiated into a neural lineage in vitro via induction with retinoic acid. These cells were then subjected to oxidative stress with a significantly high concentration of glutamate. Measurement of reactive oxygen species (ROS) was performed after inducing glutamate excitotoxicity, and recovery from this toxicity in response to vitamin E was determined. The gene expression levels of glutamate receptors and neuron-specific enolase were elucidated using real-time PCR. The results reveal that neural cells derived from 46C cells and subjected to oxidative stress exhibit downregulation of NMDA, kainate receptor, and NSE after posttreatment with different concentrations of TRF and α-TCP, a sign of neurorecovery. Treatment of either TRF or α-TCP reduced the levels of ROS in neural cells subjected to glutamate-induced oxidative stress; these results indicated that vitamin E is a potent antioxidant.

In vitro efficacy of transferrin-toxin conjugates against glioblastoma multiforme

1992 ◽  
Vol 76 (5) ◽  
pp. 838-844 ◽  
Author(s):  
Walter A. Hall ◽  
Aslak Godal ◽  
Siri Juell ◽  
Øystein Fodstad
Keyword(s):  
Glioblastoma Multiforme ◽  
Cytotoxic Activity ◽  
Cell Lines ◽  
Receptor Expression ◽  
Binding Assays ◽  
Content Type ◽  
Monensin A ◽  
Diferric Transferrin

✓ The cytotoxic activity of immunotoxins constructed with human diferric transferrin (Tfn) as the carrier ligand and an abrin variant Pseudomonas exotoxin A (PE) and the diphtheria toxin mutant cross-reacting material (CRM) 107 as the toxin moieties were studied in vitro. Three malignant human cell lines, the glioblastomas multiforme SNB19 and SF295 and the LOX melanoma, and a nonhuman control murine melanoma cell line B16 were assessed. The presence of transferrin receptors on the cell lines was confirmed by direct 125I-Tfn binding assays. The 50% protein synthesis inhibitory concentration (IC50) values for all cell lines demonstrated that Tfn-abrin variant and Tfn-PE had comparable potency and were both more effective than Tfn-CRM 107. Monensin, a carboxylic ionophore, potentiated the effect of Tfn-abrin variant against glioma cells approximately 35-fold with IC50 values of 4.0 × 10−13 M and 4.7 × 10−12 M for SNB19 and SF295, respectively. Cytotoxic activity of Tfn-abrin variant (with or without monensin) and Tfn-PE was correlated with the degree of Tfn receptor expression measured on the cell lines. The exquisite in vitro cytotoxicity of Tfn-abrin variant and Tfn-PE immunotoxins against glioma and melanoma cells warrants further in vivo evaluation and future consideration of these agents for potential clinical application against glioblastoma multiforme and leptomeningeal neoplasia.

scholarly journals Transforming growth factor-beta 1 regulates axon/Schwann cell interactions.

1995 ◽  
Vol 129 (2) ◽  
pp. 443-458 ◽  
Author(s):  
S Einheber ◽  
M J Hannocks ◽  
C N Metz ◽  
D B Rifkin ◽  
J L Salzer
Keyword(s):  
Schwann Cell ◽  
Schwann Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cell Interactions ◽  
Receptor Expression ◽  
Cell Phenotype ◽  
Beta Activity ◽  
Tgf Beta

We have investigated the potential regulatory role of TGF-beta in the interactions of neurons and Schwann cells using an in vitro myelinating system. Purified populations of neurons and Schwann cells, grown alone or in coculture, secrete readily detectable levels of the three mammalian isoforms of TGF-beta; in each case, virtually all of the TGF-beta activity detected is latent. Expression of TGF-beta 1, a major isoform produced by Schwann cells, is specifically and significantly downregulated as a result of axon/Schwann cell interactions. Treatment of Schwann cells or Schwann cell/neuron cocultures with TGF-beta 1, in turn, has dramatic effects on proliferation and differentiation. In the case of purified Schwann cells, treatment with TGF-beta 1 increases their proliferation, and it promotes a pre- or nonmyelinating Schwann cell phenotype characterized by increased NCAM expression, decreased NGF receptor expression, inhibition of the forskolin-mediated induction of the myelin protein P0, and induction of the Schwann cell transcription factor suppressed cAMP-inducible POU protein. Addition of TGF-beta 1 to the cocultures inhibits many of the effects of the axon on Schwann cells, antagonizing the proliferation induced by contact with neurons, and, strikingly, blocking myelination. Ultrastructural analysis of the treated cultures confirmed the complete inhibition of myelination and revealed only rudimentary ensheathment of axons. Associated defects of the Schwann cell basal lamina and reduced expression of laminin were also detected. These effects of TGF-beta 1 on Schwann cell differentiation are likely to be direct effects on the Schwann cells themselves which express high levels of TGF-beta 1 receptors when cocultured with neurons. The regulated expression of TGF-beta 1 and its effects on Schwann cells suggest that it may be an important autocrine and paracrine mediator of neuron/Schwann cell interactions. During development, TGF-beta 1 could serve as an inhibitor of Schwann cell proliferation and myelination, whereas after peripheral nerve injury, it may promote the transition of Schwann cells to a proliferating, nonmyelinating phenotype, and thereby enhance the regenerative response.

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