Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation

Palumbo, Paola; Lombardi, Francesca; Siragusa, Giuseppe; Dehcordi, Soheila Raysi; Luzzi, Sabino; Cimini, Annamaria; Cifone, Maria Grazia; Cinque, Benedetta

doi:10.3390/ijms19092801

Cited by 31 publications

(29 citation statements)

References 62 publications

(80 reference statements)

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“…Recently, it was reported that 1400 W significantly reduces the proliferation, migration, colony formation, and neurosphere generation ability in U‐87 MG and T98G glioma cell lines, as well as in the human glioma primary cells. This study sustains the emerging relevance of iNOS as a prognostic factor of glioma malignancy and recurrence, supporting the potential therapeutic value of safer iNOS inhibitors for a better management of this cancer …”

Section: Small Molecules Able To Downregulate Inos As Antiglioma Agentssupporting

confidence: 77%

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

et al. 2020

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Gliomas are the most prevalent primary tumors of the brain and spinal cord. Histologically, they share features of normal glial cells, but whether gliomas originate from normal glial cells, glial or neural precursors, stem cells, or other cell types remains a topic of investigation. The enhanced expression of inducible nitric oxide synthase (iNOS) has been reported as a hallmark of chemoresistance in gliomas, and several lines of evidence have reported that a decreased proliferation of glioma cells could be related to the selective inhibition of iNOS. This review aims to summarize the current understanding of iNOS expression and activity modulation in the regulation of glioma pathogenesis, along with compounds that could act as therapeutic agents against glioma.

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Section: Small Molecules Able To Downregulate Inos As Antiglioma Agentssupporting

confidence: 77%

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

et al. 2020

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“…Mixed (in vitro and in vivo in both human and mouse) Glioma cells, GSCs and blood samples [18,41] IL-6 and IL-8 partially mediated by glioma cells have a protective effect on blood neutrophils In vitro human Blood neutrophils and glioma cells [46] Depletion of neutrophils via monoclonal antibody against Ly6G prolongs the survival of mice with developing gliomas Mixed (in vitro and in vivo in mouse, and in vitro human) Transgenic mice and patients' blood [47] TANs are associated with tumor aggressiveness in mutant-IDH1 glioma Mixed (in vivo mouse and human) Transgenic mice, patients tumor tissue and blood cells/RNA [21] Primary glioma cells sustaining NOS2 activity promote proliferation, migration, and neurosphere generation and represent a prognostic factor for glioma malignancy and recurrence Human in vitro Glioma cell lines and primary culture [48] Radiation-induced infiltrating Ly6G+ neutrophils support the conversion of GBM tumor cells to GSCs via the regulation of nitrosative stress and dedifferentiation (NOS2-NO-ID4) signaling in newly diagnosed/recurrent GBM patients, and this is negatively associated with survival and radiation therapy outcomes Mixed (in vitro and in vivo in both human and mouse)…”

Section: Mixed (In Vitro and In Vivo In Both Human And Mouse)mentioning

confidence: 99%

“…Recently, it has been reported that radiation-induced senescence in GBM cells promotes the recruitment of Ly6G + (TANs) and modulates tumor microenvironmental cells and vessel formation through nuclear factor kappa-light-chain-enhancer of activated B cell (NFκB) signaling [49,67]. Palumbo et al showed that infiltrating Ly6G + cells support the conversion of GBM tumor cells to a more stem-like state through dedifferentiation and nitrosative stress (NOS2-NO-ID4) signaling [48]. Jeon et al further confirmed this mechanism by showing that NFκB inhibitors and Ly6G-neutralizing antibodies reduced the number of GSCs and prolonged the survival of tumor-bearing mice after RT [49].…”

Section: Rt Resistancementioning

confidence: 99%

“…However, direct clinical evidence establishing a clear role of TANs in the development of resistance to RT is still lacking. Moreover, it is well established that GBM tumor cells with stemness properties are resistant to RT [48,[68][69][70][71][72]. Infiltrating TANs secrete S100A4 and promote the growth of GSCs and a malignant phenotype, as well as drug resistance, in in vitro and mouse models of GBM [18].…”

Section: Rt Resistancementioning

confidence: 99%

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Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Khan

Mittal

McGee

et al. 2020

IJMS

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Recent efforts in brain tumor research have been directed towards the modulation of the immune system for therapeutic interventions. Several human cancers, including gliomas, are infiltrated with immune cell types—including neutrophils and myeloid-derived suppressor cells—that contribute to tumor progression, invasiveness, and treatment resistance. The role of tumor-associated neutrophils and myeloid-derived suppressor cells in cancer biology remains elusive, as these cells can exert a multitude of pro-tumor and antitumor effects. In this review, we provide the current understanding and novel insights on the role of neutrophils and myeloid-derived suppressor cells in glioma progression and treatment resistance, as well as the mechanisms of pleiotropic behaviors in these cells during disease progression, with an emphasis on possible strategies to reprogram these cells towards their antitumor actions.

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“…Expression of iNOS is a hallmark of chemoresistance in gliomas (brain tumors). Several studies have reported that inhibition of iNOS could be related to a decrease in proliferation of glioma cells . Based on this correlation between iNOS and gliomas, the same research group developed anti‐glioma agents by appending natural amino acids on the free –NH 2 group of 6 .…”

Section: Synthetic Inos Inhibitorsmentioning

confidence: 99%

Inducible nitric oxide synthase inhibitors: A comprehensive update

Minhas

Bansal

2019

Medicinal Research Reviews

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Inducible nitric oxide synthase (iNOS), which is expressed in response to bacterial/proinflammatory stimuli, generates nitric oxide (NO) that provides cytoprotection. Overexpression of iNOS increases the levels of NO, and this increased NO level is implicated in pathophysiology of complex multifactorial diseases like Parkinson's disease, Alzheimer's disease, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. Selective inhibition of iNOS is an effective approach in treatment of such complex diseases. L-Arginine, being a substrate for iNOS, is the natural lead to develop iNOS inhibitors. More than 200 research reports on development of nitric oxide synthase inhibitors by different research groups across the globe have appeared in literature so far. The first review on iNOS, in 2002, discussed the iNOS inhibitors under two classes that is, amino acid and non-amino acid derivatives. Other review articles discussing specific chemical classes of iNOS inhibitors also appeared during last decade. In the present review, all reports on both natural and synthetic iNOS inhibitors, published 2002 onwards, are studied, classified, and discussed to provide comprehensive information on iNOS inhibitors. The synthetic inhibitors are broadly classified into two categories that is, arginine and non-arginine analogs. The latter are further classified into amidines, five-or six-membered heterocyclics, fused cyclics, steroidal type, and chalcones analogs. Structures of the most/significantly potent compounds from each report are provided to know the functional groups important for incurring iNOS inhibitory activity and selectivity. This review is aimed to provide a comprehensive view to the medicinal chemists for rational designing of novel and potent iNOS inhibitors. K E Y W O R D S arginine, inflammation, inhibitors, multifactorial disease, nitric oxide 1 | INTRODUCTION Nitric oxide (NO) is a relaxing factor derived from endothelium, which is responsible for neuronal transmission, cardiovascular, gastrointestinal, genitourinary, respiratory, antipathogenic, and antitumor responses. The production of NO is effected by nitric oxide synthase (NOS) through catalysis of NADPH-dependent oxidation of L-arginine (the substrate). 1NOS exists in three distinct isoforms, depending on the site of its existence that is, neuronal NOS (nNOS, type I), inducible or inflammatory NOS (iNOS, type II) and endothelial NOS (eNOS, type III). Constitutive NOS are regulated by the binding of calcium-calmodulin protein, whereas iNOS is transcriptionally regulated and calcium-calmodulin independent. NO plays both physiological and pathological roles depending on the magnitude and duration of its production. 2 The physiological roles of NO are executed by soluble guanylate cyclase. Indeed, NO activates it, with the consequent increase of cyclic guanosine-3′,5′-monophosphate (cGMP) level, which subsequently activates intracellular effector molecules, cGMPdependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesteras...

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Involvement of NOS2 Activity on Human Glioma Cell Growth, Clonogenic Potential, and Neurosphere Generation

Cited by 31 publications

References 62 publications

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

Role of Neutrophils and Myeloid-Derived Suppressor Cells in Glioma Progression and Treatment Resistance

Inducible nitric oxide synthase inhibitors: A comprehensive update

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