Anti-inflammatory Effects of Atorvastatin by Suppressing TRAF3IP2 and IL-17RA in Human Glioblastoma Spheroids Cultured in a Three-dimensional Model: Possible Relevance to Glioblastoma Treatment

Bayat, Noushin; Ebrahimi‐Barough, Somayeh; Javidan, Abbas Norouzi; Saberi, Hooshang; Ardakan, Mohammad Mehdi Mokhtari; Ai, Arman; Soleimannejad, Mostafa; Ai, Jafar

doi:10.1007/s12035-017-0445-2

Cited by 15 publications

(13 citation statements)

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“…The reduction in availability of downstream products of the mevalonate pathway is thought to be a key mechanism for the observed growth inhibiting effect of different statins on different cancer cell types including glioma cells [51][52][53][54][55][56][57][58]. Downstream products of the mevalonate pathway are important for prenylation (activation) of cellular proteins Ras, Rho, and Rac, which are small GTPases critical for regulation of cell growth and survival [51].…”

Section: Statins: Atorvastatin Lovastatin Simvastatin and Pravastatinmentioning

confidence: 99%

“…Downstream products of the mevalonate pathway are important for prenylation (activation) of cellular proteins Ras, Rho, and Rac, which are small GTPases critical for regulation of cell growth and survival [51]. Other proposed mechanisms include induction of apoptosis and inhibition of cell migration: Apoptosis may be induced by altering the cellular response to stress through the Jun N-terminal kinase (JNK)-dependent cell death pathway [59], by indirectly activating Caspase-3 [56,57], or by decreasing the expression of antiapoptotic proteins such as Bcl-2 and upregulating the expression of proapoptotic proteins such as Bax and Bim [52]. Cellular migration and invasion may be inhibited through inactivation of focal adhesion kinase (FAK) [60], or decreasing the amount of extracellular matrix-degrading enzymes and matrix metalloproteinases released from microglia into the glioma environment [61].…”

Section: Statins: Atorvastatin Lovastatin Simvastatin and Pravastatinmentioning

confidence: 99%

“…Cellular migration and invasion may be inhibited through inactivation of focal adhesion kinase (FAK) [60], or decreasing the amount of extracellular matrix-degrading enzymes and matrix metalloproteinases released from microglia into the glioma environment [61]. Atorvastatin was also suggested to decrease the expression of proinflammatory proteins and interleukins (IL) [57].…”

Section: Statins: Atorvastatin Lovastatin Simvastatin and Pravastatinmentioning

confidence: 99%

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In Search of a Breakthrough Therapy for Glioblastoma Multiforme

Vasilev

Sofi

et al. 2018

Neuroglia

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Glioblastoma multiforme (GBM) is an extremely malignant type of brain cancer which originates from astrocytes or their precursors. Glioblastoma multiforme cells share some features with astrocytes but are characterized by highly unstable genomes with multiple driver mutations and aberrations. Effective therapies for GBM are lacking and hardly any progress has been made in the last 15 years in terms of improving the outcomes for patients. The lack of new especially targeted anti-GBM medications has prompted scientists in academia around the world to test whether any of the currently approved drugs might be used to fight this devastating disease. This approach is known as repurposing. Dozens of drugs have been reported to have anti-GBM properties in vitro but there is no solid evidence for the clinical efficacy of any of them. Perhaps the most interesting group of those repurposed are tricyclic antidepressants but the mechanism of their action on GBM cells remains obscure. In this brief review we consider various approaches to repurpose drugs for therapy of GBM and highlight their limitations. We also pay special attention to the mitochondria, which appear to be intimately involved in the process of apoptosis and could be a focus of future developments in search of a better treatment for patients suffering from GBM.

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Section: Statins: Atorvastatin Lovastatin Simvastatin and Pravastatinmentioning

confidence: 99%

Section: Statins: Atorvastatin Lovastatin Simvastatin and Pravastatinmentioning

confidence: 99%

Section: Statins: Atorvastatin Lovastatin Simvastatin and Pravastatinmentioning

confidence: 99%

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In Search of a Breakthrough Therapy for Glioblastoma Multiforme

Vasilev

Sofi

et al. 2018

Neuroglia

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“…Our newly developed model provides structural and histological similarities with epithelial cancers, showing the close relationship among cancer cells, CAFs, and the extracellular matrix and fibroblasts. A biomimetic model with fibrin gel is known to be an applicable 3D culture system by which to screen anticancer drug efficacy by observing changes in proliferation, invasion, and migration of cancer spheroid cells 15 , 16 . Our model involved fibrin from blood plasma that contained oral fibroblasts, which facilitate the induction of collagen and vessel formation in wounds 17 , 18 , and might provide an appropriate mimic of the tumour microenvironment in vivo .…”

Section: Discussionmentioning

confidence: 99%

Development of an in vitro cell-sheet cancer model for chemotherapeutic screening

Lee¹,

Shin²,

Roh³

2018

Theranostics

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Epithelial cancer grows in vivo in a microenvironment that comprises tumour, stroma, and immune cells. A three-dimensional (3D) culture model might be able to mimic the tumour microenvironment in vivo; therefore, we developed a new 3D epithelial cancer model using in vitro cell-sheet engineering and compared the results of treatment with several chemotherapeutic drugs among the 3D cell-sheet model, spheroid culture, and 2D cell culture.Methods: The cell sheet comprised keratinocytes and a plasma fibrin matrix containing fibroblasts. Cancer spheroids with or without cancer-associated fibroblasts (CAFs) were interposed between the keratinocytes and fibrin layer. Cell growth, viability, and hypoxia were measured using the cell counting kit-8, LIVE/DEAD assay, and propidium iodide and LOX-1 staining. The morphology, invasion, and mRNA and protein expression were compared among the different cell culture models.Results: Enhanced resistance to sorafenib and cisplatin by cancer spheroids and CAFs was more easily observed in the 3D than in the 2D model. Invasion by cancer-CAF spheroids into the fibrin matrix was more clearly observed in the 3D cell sheet. The expansion of viable cancer cells increased in the 3D cell sheet, particularly in those with CAFs, which were significantly inhibited by treatment with 10 μM sorafenib or 20 μM cisplatin (P < 0.05). TGF-β1, N-cadherin, and vimentin mRNA and protein levels were higher in the 3D cell-sheet model.Conclusions: The 3D cell sheet-based cancer model could be applied to in vitro observation of epithelial cancer growth and invasion and to anticancer drug testing.

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“…Atorvastatin enhances Tmz-induced glioma-cell death in vitro and in xenograft models. 176 Additionally, atorvastatin inhibits IL17R expression on glioma cell lines in vitro, 177 which is thought to be a keystone proglioma stem-cell effector. 178 TGFβ (specifically TGFβ 1 ) is also produced by GAMs/TAMs, and this source of cytokines has been shown to induce MMP9 expression and invasiveness of glioma stem cells in their local niche.…”

Section: Glioma-associated Microglia/macrophagesmentioning

confidence: 99%

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

Pullen¹,

Pickford²,

Perry³

et al. 2018

MNM

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Glioblastoma multiforme (GBM) remains one of the most deadly cancers, with modest advances in overall survival despite significant improvements in imaging, surgery, and molecular genomic understanding. The highest-grade glioma, GBM is a primary brain cancer that is molecularly heterogeneous among patients and even within the same patient. Key hallmarks include glioma-cell invasion, angiogenesis, and therapeutic resistance. While once considered a major player in glioma invasion, members of the MMP family are also associated with other key pathological hallmarks of glioma. Investigations into understanding MMP function in GBM were slowed due to the failed MMP-inhibitor trials for GBM in the 2000s. In contrast, the field of MMPs in other brain pathologies has flourished in such areas as traumatic brain injury, multiple sclerosis, and stroke. In the past decade, the increase in publicly available data sets documenting patient-biopsy molecular information has empowered laboratory investigations into the spectrum of genomic, transcriptomic, and proteomic changes associated with glioma, including MMPs. In this review, we selected one of these data sets to illustrate a small sample of information that can be obtained from such analyses. Combined with recent reports on the use of MMP-cleavable peptides for imaging and the multifunctionality of MMPs, including intracellular nonproteolytic actions in various cell types, this paves the way for new avenues of MMP research. Understanding the function of MMPs in host-tumor interactions both spatially and temporally during tumor progression and in response to treatment will be crucial for the advancement of targeting specific MMPs in GBM. The opportunities to explore MMP regulation, expression, and function further in GBM have never been so great with progress in modern bioinformatics and molecular techniques, and it is hoped that advancements will translate in some way to patients diagnosed with GBM.

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Anti-inflammatory Effects of Atorvastatin by Suppressing TRAF3IP2 and IL-17RA in Human Glioblastoma Spheroids Cultured in a Three-dimensional Model: Possible Relevance to Glioblastoma Treatment

Cited by 15 publications

References 50 publications

In Search of a Breakthrough Therapy for Glioblastoma Multiforme

In Search of a Breakthrough Therapy for Glioblastoma Multiforme

Development of an in vitro cell-sheet cancer model for chemotherapeutic screening

Current insights into matrix metalloproteinases and glioma progression: transcending the degradation boundary

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