The effects of chronic nitric oxide synthase suppression on glioma pathophysiology

Swaroop, G; Kelly, Paul A.; Bell, Helen; Shinoda, Jun; Yamaguchi, Shuichi; Ir, Whittle

doi:10.1080/02688690020005554

Cited by 23 publications

(2 citation statements)

References 14 publications

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“…Furthermore, elevated NO concentrations have an anti-proliferative effect and may even induce apoptosis and increase the permeability of the blood-brain barrier [ 47 ]. In vivo , the NO production by healthy adjacent tissues inhibited tumor invasion [ 48 ], regulated blood flow, and reduced tumor volume [ 49 ]. Taken together, based on our results, a mechanism of EcTI biological effects on MSC/U87 cocultures may involve the BR2, Ca 2+ influx and NO production.…”

Section: Discussionmentioning

confidence: 99%

Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer?

et al. 2018

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Glioblastoma is the most aggressive brain tumor with poor overall survival bellow 2 years. The natural compounds with anti-cancer properties, are thus gaining attention for possible adjuvant GBM treatment. In various cancer models Enterolobium contortisiliquum Trypsin Inhibitor (EcTI) proved to have anti-cancer effects. Here, we investigated the EcTI effects on GBM U87 cells and on mesenchymal stem cells (MSC) compared to their direct coculture (MSC/U87). MSC are present in tumor stroma, modulating GBM cells phenotype, and also represent potential drug delivery vehicle due to their tumor tropism. We showed that in p53-wild type U87 cells, metabolic activity was less affected by EcTI as in MSC monocuture, but the metabolic rate of mixed coculture was significantly reduced at lower EcTI concentration. Under coculture condition, EcTI potentiated MSC induced cell cycle arrest, possible due to highly increased p53, p21 and lower D1 expression, but there was no effect on apoptosis. Accordingly, in the coculture EcTI also enhanced Ca2+ signalling mediated via bradykinin receptor 2, being associated with nitric oxide release that highly impaired proliferation and invasion. The mechanism did not seem to involve changes in cell adhesion but rather it down-regulated the β1 integrin signaling with associated p-FAK in U87 cells, both supporting inhibition of invasion. Finally, some cytokines were down-regulated, indicating that EcTI inhibition of signalling might be mediated by cytokines. In conclusion, these results indicate that in cocultured MSC/U87 cells EcTI impairs the metabolic activity, proliferation, and reduced invasion, possibly associated with observed cytokines secretion. In this context, we confirmed that the plant derived protein potentiated the anticancer effects, induced by MSC, as represented by GBM U87 cell line.

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Section: Discussionmentioning

confidence: 99%

Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer?

et al. 2018

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“…It is tempting to advance the concept that blocking S-nitrosylation may be a target to fight GBM, an aggressive cancer. While NOS inhibition in rats bearing C6 glioma decreased tumor volume (Swaroop et al, 2000), specific blockade of S-nitrosylation seems to be a better alternative than blocking any and all NOS, inasmuch as genetic deletion of eNOS delayed but did not prevent development of cancer (Gratton et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-8 Secreted by Glioblastoma Cells Induces Microvascular Hyperpermeability Through NO Signaling Involving S-Nitrosylation of VE-Cadherin and p120 in Endothelial Cells

et al. 2019

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Glioblastoma is a highly aggressive brain tumor, characterized by the formation of dysfunctional blood vessels and a permeable endothelial barrier. S-nitrosylation, a post-translational modification, has been identified as a regulator of endothelial function. In this work we explored whether S-nitrosylation induced by glioblastoma tumors regulates the endothelial function. As proof of concept, we observed that S-nitrosylation is present in the tumoral microenvironment of glioblastoma in two different animal models. Subsequently, we measured S nitrosylation and microvascular permeability in EAhy296 endothelial cells and in cremaster muscle. In vitro , conditioned medium from the human glioblastoma cell line U87 activates endothelial nitric oxide synthase, causes VE-cadherin- S-nitrosylation and induces hyperpermeability. Blocking Interleukin-8 (IL-8) in the conditioned medium inhibited S-nitrosylation of VE-cadherin and hyperpermeability. Recombinant IL-8 increased endothelial permeability by activating eNOS, S-nitrosylation of VE-cadherin and p120, internalization of VE-cadherin and disassembly of adherens junctions. In vivo , IL-8 induced S-nitrosylation of VE-cadherin and p120 and conditioned medium from U87 cells caused hyperpermeability in the mouse cremaster muscle. We conclude that eNOS signaling induced by glioma cells-secreted IL-8 regulates endothelial barrier function in the context of glioblastoma involving S-nitrosylation of VE-cadherin and p120. Our results suggest that inhibiting S-nitrosylation may be an effective way to control and/or block damage to the endothelial barrier and prevent cancer progression.

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Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system

Papaevangelou

Whitley

Johnstone

et al. 2016

Intl Journal of Cancer

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Nitric oxide (NO) is a free radical signalling molecule involved in various physiological and pathological processes, including cancer. Both tumouricidal and tumour promoting effects have been attributed to NO, making its role in cancer biology controversial and unclear. To investigate the specific role of tumour-derived NO in vascular development, C6 glioma cells were genetically modified to include a doxycycline regulated gene expression system that controls the expression of an antisense RNA to inducible nitric oxide synthase (iNOS) to manipulate endogenous iNOS expression. Xenografts of these cells were propagated in the presence or absence of doxycycline. Susceptibility magnetic resonance imaging (MRI), initially with a carbogen (95% O 2 /5% CO 2 ) breathing challenge and subsequently an intravascular blood pool contrast agent, was used to assess haemodynamic vasculature (DR 2 *) and fractional blood volume (fBV), and correlated with histopathological assessment of tumour vascular density, maturation and function. Inhibition of NO production in C6 gliomas led to significant growth delay and inhibition of vessel maturation. Parametric fBV maps were used to identify vascularised regions from which the carbogeninduced DR 2 * was measured and found to be positively correlated with vessel maturation, quantified ex vivo using fluorescence microscopy for endothelial and perivascular cell staining. These data suggest that tumour-derived iNOS is an important mediator of tumour growth and vessel maturation, hence a promising target for anti-vascular cancer therapies. The combination of DR 2 * response to carbogen and fBV MRI can provide a marker of tumour vessel maturation that could be applied to non-invasively monitor treatment response to iNOS inhibitors.Nitric oxide (NO) is an important pleiotropic signalling molecule involved in physiological and pathophysiological processes, and has been detected in a variety of human tumours, including colon, breast, prostate, and brain.1,2 The effect of NO in tumours depends upon the exposure to NO in terms of duration and concentration, the intrinsic sensitivity of cells to NO, and the expression, activity and temporal distribution of the three nitric oxide synthases (NOS): neuronal (nNOS or NOS1), inducible (iNOS or NOS2), and endothelial (eNOS or NOS3) that catalyse the synthesis of NO from L-arginine. 2Tumour cells express iNOS and in some cases nNOS and eNOS, tumour-associated immune cells and stromal fibroblasts express iNOS, and vascular endothelial cells mainly express eNOS. 3The effect of NO in cancer has been the cause of intense debate due to its dichotomous nature, with studies indicating that NO has both tumour inhibitory and promoting properties.4,5 iNOS has also been implicated in tumour progression and angiogenesis. In human cancers, such as colon adenocarcinomas, 6 and central nervous system cancers, 7 increased iNOS expression and activity was positively correlated with vascularisation and higher tumour grade. In human gliomas, high iNOS expression was inver...

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The effects of chronic nitric oxide synthase suppression on glioma pathophysiology

Cited by 23 publications

References 14 publications

Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer?

Could a plant derived protein potentiate the anticancer effects of a stem cell in brain cancer?

Interleukin-8 Secreted by Glioblastoma Cells Induces Microvascular Hyperpermeability Through NO Signaling Involving S-Nitrosylation of VE-Cadherin and p120 in Endothelial Cells

Investigating the role of tumour cell derived iNOS on tumour growth and vasculature in vivo using a tetracycline regulated expression system

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