28 research outputs found
Decoy receptor DcR1 is induced in a p50/Bcl3-dependent manner and attenuates the efficacy of temozolomide
Temozolomide is used widely to treat malignant glioma but the overall response to this agent is generally poor. Resistance to DNA damaging drugs such as temozolomide has been related to the induction of anti-apoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB binding sequence (κB-site) was identified in the proximal promoter and demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance, and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy
Decoy receptor DcR1 is induced in a p50/Bcl3-dependent manner and attenuates the efficacy of temozolomide
Temozolomide is used widely to treat malignant glioma but the overall response to this agent is generally poor. Resistance to DNA damaging drugs such as temozolomide has been related to the induction of anti-apoptotic proteins. Specifically, the transcription factor NF-κB has been suggested to participate in promoting the survival of cells exposed to chemotherapy. To identify factors that modulate cytotoxicity in the setting of DNA damage, we used an unbiased strategy to examine the NF-κB-dependent expression profile induced by temozolomide. By this route, we defined the decoy receptor DcR1 as a temozolomide response gene induced by a mechanism relying upon p50/NF-κB1. A conserved NF-κB binding sequence (κB-site) was identified in the proximal promoter and demonstrated to be required for DcR1 induction by temozolomide. Loss-of-function and gain-of-function studies reveal that the atypical IκB protein, Bcl3, is also required for induction of DcR1 by temozolomide. Mechanistically, DcR1 attenuates temozolomide efficacy by blunting activation of the Fas receptor pathway in p53+/+ glioma cells. Intracranial xenograft studies show that DcR1 depletion in glioma cells enhances the efficacy of temozolomide. Taken together, our results show how DcR1 upregulation mediates temozolomide resistance, and provide a rationale for DcR1 targeting as a strategy to sensitize gliomas to this widely used chemotherapy
Convection enhanced delivery and \u3ci\u3ein vivo\u3c/i\u3e imaging of polymeric nanoparticles for the treatment of malignant glioma
A major obstacle to the management of malignant glioma is the inability to effectively deliver therapeutic agent to the tumor. In this study, we describe a polymeric nanoparticle vector that not only delivers viable therapeutic, but can also be tracked in vivo using MRI. Nanoparticles, produced by a non-emulsion technique, were fabricated to carry iron oxide within the shell and the chemotherapeutic agent, temozolomide (TMZ), as the payload. Nanoparticle properties were characterized and subsequently their endocytosis-mediated uptake by glioma cells demonstrated. Convection enhanced delivery (CED) can disperse nanoparticles through the rodent brain and their distribution is accurately visualized by MRI. Infusion of nanoparticles does not result in observable animal toxicity relative to control. CED of TMZ bearing nanoparticles prolongs the survival of animals with intracranial xenografts compared to control. In conclusion, the described nanoparticle vector represents a unique multifunctional platform that can be used for image-guided treatment of malignant glioma
NF-κB, Mesenchymal Differentiation and Glioblastoma
Although glioblastoma (GBM) has always been recognized as a heterogeneous tumor, the advent of largescale molecular analysis has enabled robust categorization of this malignancy into several specific subgroups. Among the subtypes designated by expression profiling, mesenchymal tumors have been associated with an inflammatory microenvironment, increased angiogenesis, and resistance to therapy. Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that plays a prominent role in mediating many of the central features associated with mesenchymal differentiation. This review summarizes the mechanisms by which NF-κB proteins and their co-regulating partners induce the transcriptional network that underlies the mesenchymal phenotype. Moreover, both the intrinsic changes within mesenchymal GBM cells and the microenvironmental factors that modify the overall NF-κB response are detailed
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Nuclear factor-κB in glioblastoma: insights into regulators and targeted therapy.
Nuclear factor-κB (NF-κB) is a ubiquitous transcription factor that regulates multiple aspects of cancer formation, growth, and treatment response. Glioblastoma (GBM), the most common primary malignant tumor of the central nervous system, is characterized by molecular heterogeneity, resistance to therapy, and high NF-κB activity. In this review, we examine the mechanisms by which oncogenic pathways active in GBM impinge on the NF-κB system, discuss the role of NF-κB signaling in regulating the phenotypic properties that promote GBM and, finally, review the components of the NF-κB pathway that have been targeted for treatment in both preclinical studies and clinical trials. While a direct role for NF-κB in gliomagenesis has not been reported, the importance of this transcription factor in the overall malignant phenotype suggests that more rational and specific targeting of NF-κB-dependent pathways can make a significant contribution to the management of GBM
Long-term recovery behavior of brain tissue in hydrocephalus patients after shunting
The unpredictable complexities in hydrocephalus shunt outcomes may be related to the recovery behavior of brain tissue after shunting. The simulated cerebrospinal fluid (CSF) velocity and intracranial pressure (ICP) over 15 months after shunting were validated by experimental data. The mean strain and creep of the brain had notable changes after shunting and their trends were monotonic. The highest stiffness of the hydrocephalic brain was in the first consolidation phase (between pre-shunting to 1 month after shunting). The viscous component overcame and damped the input load in the third consolidation phase (after the fifteenth month) and changes in brain volume were stopped. The long-intracranial elastance (long-IE) changed oscillatory after shunting and there was not a linear relationship between long-IE and ICP. We showed the long-term effect of the viscous component on brain recovery behavior of hydrocephalic brain. The results shed light on the brain recovery mechanism after shunting and the mechanisms for shunt failure
A New Definition for Intracranial Compliance to Evaluate Adult Hydrocephalus After Shunting
The clinical application of intracranial compliance (ICC), ∆V/∆P, as one of the most critical indexes for hydrocephalus evaluation was demonstrated previously. We suggest a new definition for the concept of ICC (long-term ICC) where there is a longer amount of elapsed time (up to 18 months after shunting) between the measurement of two values (V1 and V2 or P1 and P2). The head images of 15 adult patients with communicating hydrocephalus were provided with nine sets of imaging in nine stages: prior to shunting, and 1, 2, 3, 6, 9, 12, 15, and 18 months after shunting. In addition to measuring CSF volume (CSFV) in each stage, intracranial pressure (ICP) was also calculated using fluid–structure interaction simulation for the noninvasive calculation of ICC. Despite small increases in the brain volume (16.9%), there were considerable decreases in the ICP (70.4%) and CSFV (80.0%) of hydrocephalus patients after 18 months of shunting. The changes in CSFV, brain volume, and ICP values reached a stable condition 12, 15, and 6 months after shunting, respectively. The results showed that the brain tissue needs approximately two months to adapt itself to the fast and significant ICP reduction due to shunting. This may be related to the effect of the “viscous” component of brain tissue. The ICC trend between pre-shunting and the first month of shunting was descending for all patients with a “mean value” of 14.75 ± 0.6 ml/cm H2O. ICC changes in the other stages were oscillatory (nonuniform). Our noninvasive long-term ICC calculations showed a nonmonotonic trend in the CSFV–ICP graph, the lack of a linear relationship between ICC and ICP, and an oscillatory increase in ICC values during shunt treatment. The oscillatory changes in long-term ICC may reflect the clinical variations in hydrocephalus patients after shunting