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Biological effects of selective COX-2 inhibitor NS398 on human glioblastoma cell lines.

ABSTRACT: Background:Cyclooxygenase-2 (COX-2), an inflammation-associated enzyme, has been implicated in tumorigenesis and progression of glioblastoma (GBM). The poor survival of GBM was mainly associated with the presence of glioma stem cells (GSC) and the markedly inflammatory microenvironment. To further explore the involvement of COX-2 in glioma biology, the effects of NS398, a selective COX-2 inhibitor, were evaluated on GSC derived from COX-2 expressing GBM cell lines, i.e., U87MG and T98G, in terms of neurospheres' growth, autophagy, and extracellular vesicle (EV) release. Methods:Neurospheres' growth and morphology were evaluated by optical and scanning electron microscopy. Autophagy was measured by staining acidic vesicular organelles. Extracellular vesicles (EV), released from neurospheres, were analyzed by transmission electron microscopy. The autophagic proteins Beclin-1 and LC3B, as well as the EV markers CD63 and CD81, were analyzed by western blotting. The scratch assay test was used to evaluate the NS398 influence on GBM cell migration. Results:Both cell lines were strongly influenced by NS398 exposure, as showed by morphological changes, reduced growth rate, and appearance of autophagy. Furthermore, the inhibitor led to a functional change of EV released by neurospheres. Indeed, EV secreted by NS398-treated GSC, but not those from control cells, were able to significantly inhibit adherent U87MG and T98G cell migration and induced autophagy in recipient cells, thus leading to effects quite similar to those directly caused by NS398 in the same cells. Conclusion:Despite the intrinsic diversity and individual genetic features of U87MG and T98G, comparable effects were exerted by the COX-2 inhibitor NS398 on both GBM cell lines. Overall, our findings support the crucial role of the inflammatory-associated COX-2/PGE2 system in glioma and glioma stem cell biology.

SUBMITTER: Palumbo P

PROVIDER: S-EPMC7222447 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Biological effects of selective COX-2 inhibitor NS398 on human glioblastoma cell lines.

Palumbo Paola P Lombardi Francesca F Augello Francesca Rosaria FR Giusti Ilaria I Dolo Vincenza V Leocata Pietro P Cifone Maria Grazia MG Cinque Benedetta B

Cancer cell international 20200513

<h4>Background</h4>Cyclooxygenase-2 (COX-2), an inflammation-associated enzyme, has been implicated in tumorigenesis and progression of glioblastoma (GBM). The poor survival of GBM was mainly associated with the presence of glioma stem cells (GSC) and the markedly inflammatory microenvironment. To further explore the involvement of COX-2 in glioma biology, the effects of NS398, a selective COX-2 inhibitor, were evaluated on GSC derived from COX-2 expressing GBM cell lines, i.e., U87MG and T98G, ...[more]

PMID: 32435158

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Project description:Glioblastoma is a fatal primary malignant brain tumor, and the 5-year survival rate of treated glioblastoma patients still remains <5%. Considering the sustained development of metastasis, tumor recurrence, and drug resistance, there is an urgent need for the novel therapeutic approaches to combat glioblastoma. Trivalent arsenic derivative (arsenite, AsIII) with remarkable clinical efficacy in leukemia has been shown to exert cytocidal effect against glioblastoma cells. Gamabufotalin, an active bufadienolide compound, also shows selective cytocidal effect against glioblastoma cells, and has been suggested to serve as a promising adjuvant therapeutic agent to potentiate therapeutic effect of conventional anticancer drugs. In order to gain novel insight into therapeutic approaches against glioblastoma, the cytotoxicity of AsIII and gamabufotalin was explored in the human glioblastoma cell lines U-87 and U-251. In comparison with U-251 cells, U-87 cells were highly susceptible to the two drugs, alone or in combination. More importantly, clinically achieved concentrations of AsIII combined with gamabufotalin exhibited synergistic cytotoxicity against U-87 cells, whereas showed much less cytotoxicity to human normal peripheral blood mononuclear cells. G2/M cell cycle arrest was induced by each single drug, and further augmented by their combination in U-87 cells. Downregulation of the expression levels of cdc25C, Cyclin B1, cdc2, and survivin was observed in U-87 cells treated with the combined regimen and occurred in parallel with G2/M arrest. Concomitantly, lactate dehydrogenase leakage was also observed. Intriguingly, SB203580, a specific inhibitor of p38 MAPK, intensified the cytotoxicity of the combined regimen in U-87 cells, whereas wortmannin, a potent autophagy inhibitor, significantly rescued the cells. Collectively, G2/M arrest, necrosis and autophagy appeared to cooperatively contribute to the synergistic cytotoxicity of AsIII and gamabufotalin. Given that p38 MAPK serves an essential role in promoting glioblastoma cell survival, developing a possible strategy composed of AsIII, gamabufotalin, and a p38 MAPK inhibitor may provide novel insight into approaches designed to combat glioblastoma.

Project description:BackgroundWhether selective non-steroidal anti-inflammatory drugs (NSAIDs) has equally efficacy with non-selective NSAIDs in preventing heterotopic ossification (HO) after total hip arthroplasty (THA) was controversial. The purpose of this meta-analysis was to assess the efficacy and safety of selective NSAID versus non-selective NSAIDs for the prevention of HO after THA.MethodsPubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science, Google Search Engine, and China National Knowledge Infrastructure databases was searched for randomized controlled trials (RCTs) were comparing selective NSAID versus non-selective NSAIDs for preventing HO after THA. The primary outcomes were overall HO incidence, Brooker classification HO incidence, gastrointestinal side effects, the occurrence of excessive bleeding and discontinuation caused by gastrointestinal side effects (DGSE). Data were analyzed using Stata 12.0.ResultsA total of 8 RCTs involving 1636 patients were included in the meta-analysis. There was no significant difference between the nonselective NSAIDs group and the selective NSAIDs group in the overall incidence of HO (relative risk, RR = 0.91, 95% confidence intervals, CI 0.78-1.06, P = .203), Brooker I HO (RR = 1.02, 95% CI 0.85-1.23, P = .794), Brooker II HO (RR = 1.00, 95% CI 0.66-1.52, P = .996). Brooker III HO (RR = 0.98, 95% CI 0.37-2.62, P = .971). And the occurrence of excessive bleeding (RR = 0.67, 95% CI 0.24-1.92, P = .458). The selective NSAIDs group was associated with a significant decrease in gastrointestinal side effects (RR = 0.35, 95% CI 0.18-0.71, P = .004) and discontinuation caused by gastrointestinal side effects compared with the nonselective NSAIDs group (RR = 0.28, 95% CI 0.11-0.66, P = .004).ConclusionThe available evidence indicates selective NSAIDs were as effective as non-selective NSAIDs in preventing HO after THA. And selective NSAIDs were associated with less gastrointestinal side effects than non-selective NSAIDs. Considering the limitation of current meta-analysis, more RCTs need to identify the optimal NSAIDs drug for HO after THA.

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Biological effects of selective COX-2 inhibitor NS398 on human glioblastoma cell lines.

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Biological effects of selective COX-2 inhibitor NS398 on human glioblastoma cell lines.

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