NFκB inhibitors induce cell death in glioblastomas

Zanotto-Filho, Alfeu; Braganhol, Elizandra; Schröder, Rafael; Souza, Luís Henrique Trentin de; Dalmolin, Rodrigo Juliani Siqueira; Pasquali, Matheus A.B.; Gelain, Daniel Pens; Battastini, Ana Maria Oliveira; Moreira, José Cláudio Fonseca

doi:10.1016/j.bcp.2010.10.014

Cited by 112 publications

(94 citation statements)

References 63 publications

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“…Although the association between NF-kB pathway activation and GBM aggressiveness and chemoresistance as well as NF-kB as a therapeutic target is known (24,28), our study clearly shows that NF-kB pathway is activated particularly in high-risk group. Our data also show that NF-kB inhibition could sensitize only those glioma cells having activated NF-kB pathway to chemotherapy.…”

Section: Discussionmentioning

confidence: 86%

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

et al. 2013

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Glioblastoma (GBM) is the most common, malignant adult primary tumor with dismal patient survival, yet the molecular determinants of patient survival are poorly characterized. Global methylation profile of GBM samples (our cohort; n ¼ 44) using high-resolution methylation microarrays was carried out. Cox regression analysis identified a 9-gene methylation signature that predicted survival in GBM patients. A risk-score derived from methylation signature predicted survival in univariate analysis in our and The Cancer Genome Atlas (TCGA) cohort. Multivariate analysis identified methylation risk score as an independent survival predictor in TCGA cohort. Methylation risk score stratified the patients into low-risk and high-risk groups with significant survival difference. Network analysis revealed an activated NF-kB pathway association with high-risk group. NF-kB inhibition reversed glioma chemoresistance, and RNA interference studies identified interleukin-6 and intercellular adhesion molecule-1 as key NF-kB targets in imparting chemoresistance. Promoter hypermethylation of neuronal pentraxin II (NPTX2), a risky methylated gene, was confirmed by bisulfite sequencing in GBMs. GBMs and glioma cell lines had low levels of NPTX2 transcripts, which could be reversed upon methylation inhibitor treatment. NPTX2 overexpression induced apoptosis, inhibited proliferation and anchorage-independent growth, and rendered glioma cells chemosensitive. Furthermore, NPTX2 repressed NF-kB activity by inhibiting AKT through a p53-PTENdependent pathway, thus explaining the hypermethylation and downregulation of NPTX2 in NF-kB-activated highrisk GBMs. Taken together, a 9-gene methylation signature was identified as an independent GBM prognosticator and could be used for GBM risk stratification. Prosurvival NF-kB pathway activation characterized high-risk patients with poor prognosis, indicating it to be a therapeutic target. Cancer Res; 73(22); 6563-73. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 86%

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

et al. 2013

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“…Primary astrocytes were isolated from cortex of 2-days old Wistar rats by mechanical dissociation with Ca +2 /Mg +2 -free Hank's balanced salt solution, and plated in poly-L-lysine-coated plates as described [11]. The cells were maintained in low-glucose DMEM plus antibiotics (Gibco BRL, Carlsbad, USA) in a humidified incubator.…”

Section: Cell Linesmentioning

confidence: 99%

Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas

et al. 2015

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Glioblastoma is a devastating primary brain tumor resistant to conventional therapies. In this study, we tested the efficacy of combining temozolomide with curcumin, a phytochemical known to inhibit glioblastoma growth, and investigated the mechanisms involved. The data showed that synergy between curcumin and temozolomide was not achieved due to redundant mechanisms that lead to activating protective autophagy both in vitro and in vivo. Autophagy preceded apoptosis, and blocking this response with autophagy inhibitors (3-methyl-adenine, ATG7 siRNA and chloroquine) rendered cells susceptible to temozolomide and curcumin alone or combinations by increasing apoptosis. While curcumin inhibited STAT3, NFκB and PI3K/Akt to affect survival, temozolomide-induced autophagy relied on the DNA damage response and repair components ATM and MSH6, as well as p38 and JNK1/2. However, the most interesting observation was that both temozolomide and curcumin required ERK1/2 to induce autophagy. Blocking this ERK1/2-mediated temozolomide and curcumin induced autophagy with resveratrol, a blood-brain barrier permeable drug, improved temozolomide/curcumin efficacy in brain-implanted tumors. Overall, the data presented demonstrate that autophagy impairs the efficacy of temozolomide/curcumin, and inhibiting this phenomenon could provide novel opportunities to improve brain tumor treatment.

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“…Afterwards, cells were incubated for at least 10 minutes on ice for cell lysis (10 6 cells/mL lysis buffer). 27 The DNA content was determined by flow cytometry (FACSCalibur; BD Biosciences). Ten thousand events were counted per sample.…”

Section: Cell-cycle Analysismentioning

confidence: 99%

The antiproliferative effect of indomethacin-loaded lipid-core nanocapsules in glioma cells is mediated by cell cycle regulation, differentiation, and the inhibition of survival pathways

Bernardi¹,

Frozza²,

Hoppe³

et al. 2013

IJN

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Despite recent advances in radiotherapy, chemotherapy, and surgical techniques, glioblastoma multiforme (GBM) prognosis remains dismal. There is an urgent need for new therapeutic strategies. Nanoparticles of biodegradable polymers for anticancer drug delivery have attracted intense interest in recent years because they can provide sustained, controlled, and targeted delivery. Here, we investigate the mechanisms involved in the antiproliferative effect of indomethacin-loaded lipid-core nanocapsules (IndOH-LNC) in glioma cells. IndOH-LNC were able to reduce cell viability by inducing apoptotic cell death in C6 and U138-MG glioma cell lines. Interestingly, IndOH-LNC did not affect the viability of primary astrocytes, suggesting that this formulation selectively targeted transformed cells. Mechanistically, IndOH-LNC induced inhibition of cell growth and cell-cycle arrest to be correlated with the inactivation of AKT and β-catenin and the activation of GSK-3β. IndOH-LNC also induced G0/G1 and/or G2/M phase arrest, which was accompanied by a decrease in the levels of cyclin D1, cyclin B1, pRb, and pcdc2 and an increase in the levels of Wee1 CDK inhibitor p21 WAF1. Additionally, IndOH-LNC promoted GBM cell differentiation, observed as upregulation of glial fibrillary acidic protein (GFAP) protein and downregulation of nestin and CD133. Taken together, the crosstalk among antiproliferative effects, cell-cycle arrest, apoptosis, and cell differentiation should be considered when tailoring pharmacological interventions aimed at reducing glioma growth by using formulations with multiples targets, such as IndOH-LNC.

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NFκB inhibitors induce cell death in glioblastomas

Cited by 112 publications

References 63 publications

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

A DNA Methylation Prognostic Signature of Glioblastoma: Identification of NPTX2-PTEN-NF-κB Nexus

Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas

The antiproliferative effect of indomethacin-loaded lipid-core nanocapsules in glioma cells is mediated by cell cycle regulation, differentiation, and the inhibition of survival pathways

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