PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression in vitro and in vivo

Publication date: Available online 18 September 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Fangfang Li, Zongliang Liu, Heyuan Sun, Chunmei Li, Wenyan Wang, Liang Ye, Chunhong Yan, Jingwei Tian, Hongbo WangAbstractGliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. In vitro, PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an in vivo glioma model, PCC0208017 showed robust anti-tumor activity, blood–brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.Graphical abstractPCC0208017 inhibits the activity of MARK3 and MARK4 and suppresses the growth, migration and invasion of glioma cells, as well as inhibit the angiogenesi...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research

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Previous central nervous systems Oncology Scan articles in this publication have discussed treatment and molecular characterization of low-,1 intermediate-,2 and high-grade3,4 gliomas, controversies in the management of brain metastases,5-8 and evolving approaches to atypical meningiomas.9 Although arteriovenous malformations (AVMs) are nononcologic entities, optimal management of patients with this disease presents many of the same questions involved in the treatment of low-grade tumors: when, whom, or even if to treat.
Source: International Journal of Radiation Oncology * Biology * Physics - Category: Radiology Authors: Tags: Feature Source Type: research
Publication date: Available online 22 October 2019Source: Nanomedicine: Nanotechnology, Biology and MedicineAuthor(s): Muhammad Younis, Wang Faming, Zhao Hongyan, Tan Mengmeng, Song Hang, Yuan LiudiAbstractGlioma is the most common neoplasm of the central nervous system, with the highest mortality rate. The present study was designed to examine the therapeutic effect of Iguratimod (IGU) encapsulated- poly (lactic-co-glycolic acid) PLGA nanoparticles (IGU-PLGA-NPs), which showed inhibition of glioma cells proliferation both in vitro and in vivo. IGU was encapsulated in PLGA nanoparticles with an average size of 100-200 nm w...
Source: Nanomedicine: Nanotechnology, Biology and Medicine - Category: Nanotechnology Source Type: research
In this study, biotinylated PAMAM G3 dendrimers substituted with the recognized anticancer agents cyclooxygenase-2 (COX-2) inhibitor celecoxib and peroxisome proliferator-activated receptor γ (PPARγ) agonist Fmoc-L-Leucine (G3-BCL) were tested in vitro on human cell lines with different p53 status: glioblastoma (U-118 MG), normal fibroblasts (BJ) and immortalized keratinocytes (HaCaT). G3-BCL penetrated efficiently into the lysosomal and mitochondrial compartments of U-118 MG cells and induced death of U-118 MG cells via apoptosis and inhibited proliferation and migration at low IC50 = 1.25 µM...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
CCR Grand Rounds Dr. Jabado ’ s research focuses on elucidating genetic signatures of pediatric astrocytomas and examining how they compare to adults. These are deadly brain tumors that originate in the brain and include glioblastomas (GBM, the highest grade of astrocytomas), which are one of the deadliest cancers in humans. Her group uncovered that pediatric high-grade astrocytomas (HGA) are molecularly and genetically distinct from adult tumors. They also identified a new molecular mechanism driving pediatric HGA, namely recurrent somatic driver mutations in the tail of histone 3 variants (H3.3 and H3.1). These mut...
Source: Videocast - All Events - Category: General Medicine Tags: Upcoming Events Source Type: video
Conclusions. In summary, RES529, the first dual TORC1/TORC2 dissociative inhibitor, lacking affinity for ABCB1/ABCG2 and having good brain penetration, was active in GBM preclinical/murine models giving credence to its use in clinical trial for patients with GBM treated in association with anti-angiogenetic compounds.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Publication date: Available online 19 October 2019Source: NeuroImage: ClinicalAuthor(s): Binke Yuan, Nan Zhang, Jing Yan, Jingliang Cheng, Junfeng Lu, Jinsong WuAbstractLanguage deficits following brain tumors should consider the dynamic interactions between different tumor growth kinetics and functional network reorganization. We measured the resting-state functional connectivity of 126 patients with left cerebral gliomas involving language network areas, including 77 patients with low-grade glioma (LGG) and 49 patients with high-grade glioma (HGG). Functional network mapping for language was performed by construction of ...
Source: NeuroImage: Clinical - Category: Radiology Source Type: research
Parents of Abbie Mifsud created the charity that has funded vital research on brain stem tumoursResearchers say they are close to testing a drug that could tackle a previously untreatable childhood brain cancer. The condition is known as DIPG – diffuse intrinsic pontine glioma – and every year it affects between 30 to 40 boys and girls, aged between five and 10. All develop tumours caused by the condition and die, often within months of their diagnoses.But now scientists believe they may soon be able to tackle the condition – and one of the key organisations involved is a remarkable charity set up by Aman...
Source: Guardian Unlimited Science - Category: Science Authors: Tags: Drugs Health Science Society UK news Source Type: news
Authors: Suo F, Zhong B, Lu F, Dong Z Abstract Glioma is the most aggressive brain tumor and is associated with a high mortality rate. The aim of the present study was to explore the association between matrix metalloproteinase 2 (MMP-2) and ephrin type-A receptor 2 (EphA2) expression in glioma cells, and to investigate the contribution of magnetic resonance imaging (MRI) in glioma classification. A total of 43 patients with pathologically confirmed glioma were divided into two groups as follows: Low-grade (grades I and II; n=21) and high-grade (grades IV and IV; n=22). Subsequently, immunohistochemistry staining w...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
A radiation therapy (RT) treatment that combines radiation with chemotherapy...Read more on AuntMinnie.comRelated Reading: Intelerad to launch enterprise software at RANZCR 2019 RANZCR issues final version of ethical AI guidelines RANZCR praises government pledge to support MRI access RANZCR proposes ethical guidelines for AI Virtual reality may help plan, guide glioma resection
Source: AuntMinnie.com Headlines - Category: Radiology Source Type: news
Purpose Gliomas constitute the most frequent primary brain tumors. Glioblastoma, the most common and malignant glioma in adults, has dismal prognosis with any current therapy. On the other hand, low-grade gliomas, the second most common type of gliomas, are potentially curative with appropriate treatment. Methods We conducted a meta-analysis to assess the performance of PET tracers with the best available evidence, namely, fluorodeoxyglucose (FDG), 11C-methionine (MET), and 18F-fluoroethyltyrosine (FET), in differentiating low- from high-grade gliomas. Results Twenty-three studies with a total of 994 participants w...
Source: Clinical Nuclear Medicine - Category: Nuclear Medicine Tags: Original Articles Source Type: research
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