scholarly journals CYT387, a potent IKBKE inhibitor, suppresses human glioblastoma progression by activating the Hippo pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xin Wang ◽  
Jie Lu ◽  
Jing Li ◽  
Yang Liu ◽  
Gaochao Guo ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Blood Brain Barrier ◽  
Hippo Pathway ◽  
Brain Barrier ◽  
Migration And Invasion ◽  
Mouse Tumor ◽  
Glioblastoma Cell ◽  
Blood Brain ◽  
The Hippo Pathway

AbstractRecent studies have showed that IKBKE is overexpressed in several kinds of cancers and that IKBKE-knockdown inhibits tumor progression. In this article, we first verified that two glioblastoma cell lines, U87-MG and LN-229, were sensitive to CYT387 by measuring the half maximal inhibitory concentration (IC50) with a CCK-8 assay and then demonstrated that CYT387, as a potent IKBKE inhibitor, suppressed glioblastoma cell proliferation, migration and invasion. Additionally, CYT387 induced cell apoptosis and arrested the cell cycle at the G2/M checkpoint in vitro. Furthermore, we showed that CYT387 did not simply inhibit IKBKE activity but also decreased IKBKE expression at the protein level rather than at the mRNA level. We discovered that CYT387 restrained malignant tumor progression by activating the Hippo pathway in vitro. By coimmunoprecipitation (co-IP), we showed that IKBKE interacted with TEAD2 and YAP1, thus accelerating TEAD2 and YAP1 transport into the nucleus. In subsequent in vivo experiments, we found that CYT387 inhibited subcutaneous nude mouse tumor growth but had little impact on intracranial orthotopic xenografts, probably due to a limited ability to penetrate the blood–brain barrier (BBB). These results suggest that CYT387 has potential as a new antiglioblastoma drug, but an approach to allow passage through the blood–brain barrier (BBB) is needed.

scholarly journals Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Joni Merisaari ◽  
Oxana V Denisova ◽  
Milena Doroszko ◽  
Vadim Le Joncour ◽  
Patrik Johansson ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Cell Lines ◽  
Small Molecule ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Brain Barrier ◽  
Glioblastoma Cell ◽  
Blood Brain ◽  
Phosphatase 2A

Abstract Glioblastoma is a fatal disease in which most targeted therapies have clinically failed. However, pharmacological reactivation of tumour suppressors has not been thoroughly studied as yet as a glioblastoma therapeutic strategy. Tumour suppressor protein phosphatase 2A is inhibited by non-genetic mechanisms in glioblastoma, and thus, it would be potentially amendable for therapeutic reactivation. Here, we demonstrate that small molecule activators of protein phosphatase 2A, NZ-8-061 and DBK-1154, effectively cross the in vitro model of blood–brain barrier, and in vivo partition to mouse brain tissue after oral dosing. In vitro, small molecule activators of protein phosphatase 2A exhibit robust cell-killing activity against five established glioblastoma cell lines, and nine patient-derived primary glioma cell lines. Collectively, these cell lines have heterogeneous genetic background, kinase inhibitor resistance profile and stemness properties; and they represent different clinical glioblastoma subtypes. Moreover, small molecule activators of protein phosphatase 2A were found to be superior to a range of kinase inhibitors in their capacity to kill patient-derived primary glioma cells. Oral dosing of either of the small molecule activators of protein phosphatase 2A significantly reduced growth of infiltrative intracranial glioblastoma tumours. DBK-1154, with both higher degree of brain/blood distribution, and more potent in vitro activity against all tested glioblastoma cell lines, also significantly increased survival of mice bearing orthotopic glioblastoma xenografts. In summary, this report presents a proof-of-principle data for blood–brain barrier—permeable tumour suppressor reactivation therapy for glioblastoma cells of heterogenous molecular background. These results also provide the first indications that protein phosphatase 2A reactivation might be able to challenge the current paradigm in glioblastoma therapies which has been strongly focused on targeting specific genetically altered cancer drivers with highly specific inhibitors. Based on demonstrated role for protein phosphatase 2A inhibition in glioblastoma cell drug resistance, small molecule activators of protein phosphatase 2A may prove to be beneficial in future glioblastoma combination therapies.

scholarly journals Development of curcumin-loaded zein nanoparticles for transport across the blood–brain barrier and inhibition of glioblastoma cell growth

2021 ◽  
Author(s):  
Huaiying Zhang ◽  
Winant L. van Os ◽  
Xiaobo Tian ◽  
Guangyue Zu ◽  
Laís Ribovski ◽  
...  
Keyword(s):  
Cell Growth ◽  
Blood Brain Barrier ◽  
Glioma Cells ◽  
C6 Glioma ◽  
Brain Barrier ◽  
C6 Glioma Cells ◽  
Glioblastoma Cell ◽  
Tumor Spheroids ◽  
Blood Brain

Zein-polydopamine nanoparticles functionalized with G23 peptide cross an in vitro blood–brain barrier and penetrate tumor spheroids. When loaded with curcumin they effectively reduce proliferation, migration, and viability of C6 glioma cells.

scholarly journals Biochemical‐ and Biophysical‐Induced Barriergenesis in the Blood–Brain Barrier: A Review of Barriergenic Factors for Use in In Vitro Models

2021 ◽  
Vol 1 (5) ◽  
pp. 2170051
Author(s):  
Christina L. Schofield ◽  
Aleixandre Rodrigo-Navarro ◽  
Matthew J. Dalby ◽  
Tom Van Agtmael ◽  
Manuel Salmeron-Sanchez
Keyword(s):  
Blood Brain Barrier ◽  
In Vitro Models ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Miniaturization and Automation of a Human In Vitro Blood–Brain Barrier Model for the High-Throughput Screening of Compounds in the Early Stage of Drug Discovery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 892
Author(s):  
Elisa L. J. Moya ◽  
Elodie Vandenhaute ◽  
Eleonora Rizzi ◽  
Marie-Christine Boucau ◽  
Johan Hachani ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Blood Brain Barrier ◽  
Early Stage ◽  
Molecular Transport ◽  
Brain Barrier ◽  
Blood Brain ◽  
Cns Drugs ◽  
The Impact ◽  
The Brain

Central nervous system (CNS) diseases are one of the top causes of death worldwide. As there is a difficulty of drug penetration into the brain due to the blood–brain barrier (BBB), many CNS drugs treatments fail in clinical trials. Hence, there is a need to develop effective CNS drugs following strategies for delivery to the brain by better selecting them as early as possible during the drug discovery process. The use of in vitro BBB models has proved useful to evaluate the impact of drugs/compounds toxicity, BBB permeation rates and molecular transport mechanisms within the brain cells in academic research and early-stage drug discovery. However, these studies that require biological material (animal brain or human cells) are time-consuming and involve costly amounts of materials and plastic wastes due to the format of the models. Hence, to adapt to the high yields needed in early-stage drug discoveries for compound screenings, a patented well-established human in vitro BBB model was miniaturized and automated into a 96-well format. This replicate met all the BBB model reliability criteria to get predictive results, allowing a significant reduction in biological materials, waste and a higher screening capacity for being extensively used during early-stage drug discovery studies.

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