Targeting iNOS As a Valuable Strategy for the Therapy of Glioma

Abstract

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.

Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

“…Studies also revealed that lower amount of nitric oxide (NO) produced through inducible nitric oxide synthase (iNOS/NOS2) in various tumors, including gliomas, can promote angiogenesis, invasion, and cellular proliferation ( Fahey and Girotti, 2019 ; Maccallini et al, 2020 ). iNOS is a key regulator of glioma transformation downstream of the EGFRvIII/STAT3 signaling pathway.…”

“…STAT3 directly binds to the promoter of the iNOS and thereby stimulates its expression ( Jahani-Asl and Bonni, 2013 ). Moreover, iNOS-derived NO in glioma cells elicits resistance to various therapies including 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) and endows gliomas of greater proliferation and aggressiveness ( Fahey and Girotti, 2019 ; Maccallini et al, 2020 ). Several lines of evidence have showed that decreased proliferation of glioma cells could be mediated by selective inhibition of iNOS such as 1,400 W (N-(3-(aminomethyl) benzyl) acetamidine) ( Fedorov et al, 2003 ) or mercapto-ethyl guanidine (MEG) ( Southan et al, 1996 ) which inhibit the iNOS activity.…”

Circular RNA: A novel type of biomarker for glioma (Review)

“…Glioma is the most prevalent type of primary tumor of the central nervous system and accounts for >75% of malignant brain tumors (1,2). Histologically, glial-derived tumors, or gliomas, share characteristics of normal glial cells, glial or neural precursors and stem cells, and are generally named based on these similarities (3)(4)(5). Recent advances in molecular understanding have provided new insights and novel molecular subclassification of gliomas.…”

A Novel Prodrug of a nNOS Inhibitor with Improved Pharmacokinetic Potential

“…[12,13] Also iNOS induction can cause inflammatory and autoimmune diseases, including septic shock, rheumatoid arthritis, diabetes, multiple sclerosis, and cancer. [14,15] The possibility of treating pathological conditions by selective inhibition of nNOS and iNOS could represent a feasible therapeutic strategy, and has stimulated an intense research effort. [16,17] On the contrary, NO produced by eNOS has mainly a physiological role, especially in maintaining vascular tone, and its inhibition should be avoided.…”

“…In mammalian cells, aberrant nNOS induction can have detrimental consequences linked to the overproduction of NO, generating peroxynitrite and nitrosothiols; these highly reactive species can cause irreversible cell damage in excitotoxicity, ischemia, Parkinson's disease, Alzheimer's disease and depression [12,13] . Also iNOS induction can cause inflammatory and autoimmune diseases, including septic shock, rheumatoid arthritis, diabetes, multiple sclerosis, and cancer [14,15] . The possibility of treating pathological conditions by selective inhibition of nNOS and iNOS could represent a feasible therapeutic strategy, and has stimulated an intense research effort [16,17] .…”