Exploitation of a novel phenothiazine derivative for its anti-cancer activities in malignant glioblastoma

This study adopts a drug repurposing approach by investigating the anti-cancer activity of a derivative of the antipsychotic drug phenothiazine (DS00329) in malignant U251 and U87 glioblastoma cells. Results from MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays showed that DS00329 inhibited short-term glioblastoma cell viability and long-term survival while sparing non-cancerous cells. Western  blot analysis with an antibody to γH2AX showed that DS00329 induced DNA damage and flow cytometry and western blotting confirmed that it triggered a G1 cell cycle arrest which correlated with decreased levels in Cyclin A, Cyclin B, Cyclin D1 and cyclin dependent kinase 2 and an increase in levels of the cyclin dependent kinase inhibitor p21. DS00329 treated glioblastoma cells exhibited morphological and molecular markers typical of apoptotic cells such as membrane blebbing and cell shrinkage and an increase in levels of cleaved PARP. Flow cytometry with annexin V-FITC/propidium iodide stain ing confirmed that DS00329 induced apoptotic cell death in glioblastoma cells. We also show that DS00329 treatment of glioblastoma cells led to an increase in the autophagosome marker LC3-II and autophagy inhibition studies using bafilomycin A1 and wortmannin, showed that DS00329-induced-autophagy w as a pro-death mechanism. Furthermore, DS00329 treatment of glioblastoma cells inhibited the phosphatidylinositol 3′-kinase/Akt cell survival path...
Source: Apoptosis - Category: Molecular Biology Source Type: research

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A machine learning model developed by Yale ’s Dr. Murat Günel makes predictions to help doctors diagnose the stage of brain cancers faster and more accurately.
Source: Yale Science and Health News - Category: Universities & Medical Training Source Type: news
Conclusion: Although cases of metastatic intradural extramedullary spinal tumors from ovarian cancer are extremely rare, their possibility should be considered in the differential diagnosis. A history of brain metastases and enhancement on T1-weighted MRI were helpful for making an accurate diagnosis. PMID: 32202486 [PubMed - as supplied by publisher]
Source: Journal of Spinal Cord Medicine - Category: Orthopaedics Tags: J Spinal Cord Med Source Type: research
Gliomas are complex and heterogeneous brain tumors with poor prognosis. Glioma cells can communicate with their surroundings to create a tumor-permissive microenvironment. Exosomes represent a new means of int...
Source: Molecular Cancer - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Hadden While loss-of-function mutations in the ATRX gene have been implicated as a driving force for a variety of pediatric brain tumors, as well as pancreatic neuroendocrine tumors, the role of ATRX in gene regulation and oncogenic development is not well-characterized. The ADD domain of ATRX (ATRXADD) localizes the protein to chromatin by specifically binding to the histone H3 tail. This domain is also a primary region that is mutated in these cancers. The overall goal of our studies was to utilize a variety of techniques (experimental and computational) to probe the H3:ATRXADD protein-protein interaction (PPI). We d...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
Expression of neuropeptides and their corresponding receptors has been demonstrated in different cancer types, where they can play a role in tumor cell growth, invasion, and migration. Human galanin (GAL) is a 30-amino-acid regulatory neuropeptide which acts through three G protein-coupled receptors, GAL1-R, GAL2-R, and GAL3-R that differ in their signal transduction pathways. GAL and galanin receptors (GALRs) are expressed by different tumors, and direct involvement of GAL in tumorigenesis has been shown. Despite its strong expression in the central nervous system (CNS), the role of GAL in CNS tumors has not been extensiv...
Source: Frontiers in Endocrinology - Category: Endocrinology Source Type: research
CONCLUSIONS: For elderly people with glioblastoma who are self-caring, evidence suggests that CRT prolongs survival compared with RT and may prolong overall survival compared with TMZ alone. For those undergoing RT or TMZ therapy, there is probably little difference in QoL overall. Systemic anti-cancer treatments TMZ and BEV carry a higher risk of severe haematological and thromboembolic events and CRT is probably associated with a higher risk of these events. Current evidence provides little justification for using BEV in elderly patients outside a clinical trial setting. Whilst the novel TTF device appears prom...
Source: Cochrane Database of Systematic Reviews - Category: General Medicine Authors: Tags: Cochrane Database Syst Rev Source Type: research
This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
in Geurts Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspe...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Perspective Source Type: research
Conclusion: Experimental results demonstrate both complexity and performance benefits of the ALSF over state-of-the-art alternatives. Significance: Modeling shared features with appropriate quantitative constraints lead to significantly improved classification in histopathology.
Source: IEEE Transactions on Biomedical Engineering - Category: Biomedical Engineering Source Type: research
We examined the effects of NOC-18, an NO donor, on the expression of PD-L1 in A172 glioblastoma cells. NOC-18 increased PD-L1 expression in A172 glioblastoma cells. Moreover, this increase is regulated via the JNK pathway. PMID: 32201424 [PubMed - as supplied by publisher]
Source: Biological and Pharmaceutical Bulletin - Category: Drugs & Pharmacology Authors: Tags: Biol Pharm Bull Source Type: research
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