Malignant glioma progression and nitric oxide

doi:10.1016/j.neuint.2006.07.001

Neurochemistry International

Volume 49, Issue 8, December 2006, Pages 764-768

https://doi.org/10.1016/j.neuint.2006.07.001 Get rights and content

Abstract

Glioblastoma multiforme, the most common of the malignant gliomas, carries a dismal prognosis in spite of the most aggressive therapy and recent advances in molecular pathways of glioma progression. Although it has received relatively little attention in the setting of malignant gliomas, nitric oxide metabolism may be intimately associated with the disease process. Interestingly, nitric oxide has both physiological roles (e.g., neurotransmitter-like activity, stimulation of cyclic GMP), and pathophysiological roles (e.g., neoplastic transformation, tumor neovascularization, induction of apoptosis, free radical damage). Moreover, whether nitric oxide is neuroprotective or neurotoxic in a given disease state, or whether it enhances or diminishes chemotherapeutic efficacy in malignant neoplasia, is unresolved. This review discusses the multifaceted activity of nitric oxide with particular reference to malignant gliomas.

Section snippets

Malignant gliomas—the problem

Malignant gliomas comprise the majority of 20,000 primary brain tumors diagnosed each year in the United States (Louis et al., 2002). Of these, glioblastoma multiforme (GBM) is the most common and has the poorest prognosis. In spite of recent advances in molecular genetics and improved understanding of glioma progression, the 5-year survival of glioblastoma remains at about 1% (Davis et al., 1998). Average survival, even with the most aggressive therapy (surgery plus radiation therapy plus

Molecular genetics of glioma progression—background information

The molecular genetics of glioblastoma encompasses two main pathways: primary and secondary. Primary glioblastoma has a short clinical course, arising de novo, without a precursor lesion. Secondary glioblastomas develop more slowly, arising from a lower grade astrocytoma (Kleihues and Ohgaki, 2000, Kleihues et al., 2002, Ohgaki et al., 2004).

The most frequent genetic modification in glioblastomas (60–80%) is loss of heterozygosity (LOH) on chromosome 10 (Karlbom et al., 1993, Ohgaki et al., 1995

Nitric oxide and nitric oxide synthase in malignant gliomas

There has been much interest in the roles nitric oxide (NO) may play in the pathogenesis of GBM. Nitric oxide is produced by a group of enzymes called nitric oxide synthases. There are three isoforms of nitric oxide synthase (NOS) named according to their activity or the tissue type in which they were first described. The isoforms of NOS are neuronal NOS (or nNOS), endothelial NOS (or eNOS), and inducible NOS (or iNOS). NO is generated by iNOS following exposure to certain cytokines. Induction

Does nitric oxide affect chemotherapeutic agents?

Chemotherapy for malignant gliomas (Louis et al., 2002) usually includes compounds from the chloroethylnitrosurea family (BCNU, CCNU), as well as temozolomide, which has lesser toxicity. Intravenous PCV therapy (a combination of procarbazine, CCNU, and vincristine) has been shown to be particularly effective against anaplastic oligodendroglioma, a glioma subtype now characterized by allelic loss of chromsome 1p and 19q which, for reasons not yet elucidated, appears to confer chemosensitivity

Summary

The apparent multiplicity of roles for NO in malignancies is evident in this review of GBM. Given the complexities associated with the molecular genetics of GBM pathogenesis, NO is likely to play different roles within the subtypes of GBM, which may further diverge dependent on the stage of disease. We have observed that the influence of NO generation within a biological system is chiefly dependent on the level of NO formation, the duration of exposure and the redox microenvironment (Wink and

Acknowledgments

Work in the authors’ laboratories is supported by the National Institutes of Health, the Alzheimer's Association, Philip Morris USA Inc. and Philip Morris International.

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Low level nitric oxide (NO) produced by inducible NO synthase (iNOS) in many malignant tumors is known to play a key role in the survival and proliferation of tumor cells. NO can also induce or augment resistance to anti-tumor treatments such as platinum-based chemotherapy (CT), ionizing radiotherapy (RT), and non-ionizing photodynamic therapy (PDT). In each of these treatments, tumor cells that survive the challenge may exhibit a striking increase in NO-dependent proliferative, migratory, and invasive aggressiveness compared with non-challenged controls. Moreover, NO from cells directly targeted by PDT can often stimulate aggressiveness in non- or poorly targeted bystander cells. Although NO-mediated resistance to many of these therapies is fairly-well recognized by now, the hyper-aggressiveness of surviving cells and bystander counterparts is not. We will focus on these negative aspects in this review, citing examples from the PDT, CT, and RT publications. Increased aggressiveness of cells that escape therapeutic elimination is a concern because it could enhance tumor progression and metastatic dissemination. Pharmacologic approaches for suppressing these negative responses will also be discussed, e.g., administering inhibitors of iNOS activity or iNOS expression as therapeutic adjuvants.
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The metabolic pathways linking Arg to NO and polyamines are illustrated in Fig. 1. While the pleiotropic roles of NO [11,12] and polyamines [13] in shaping the phenotype of peripheral tumors have been a subject of recent exhaustive reviews, no focused updates on the status of these molecules in brain tumors have appeared in the last few decades [14,15]. Among the multitude of immediate or distant Arg metabolites, only the ones here considered have so far been convincingly implicated in critical stages of brain tumor initiation, growth or invasion.
Nitric oxide (NO) and polyamines: putrescine, spermidine and spermine, are key arginine metabolites in mammalian tissues that play critical roles i.a. in regulation of vascular tone (NO), and cell cycle regulation (polyamines). In the brain, both classes of molecules additionally have neuromodulatory and neuroprotective potential, and NO also a neurotoxic potential. Here we review evidence that brain tumors use the NO- and polyamine-synthesizing machineries to the benefit of their differentiation and growth from healthy glia and neurons. With a few exceptions, brain tumors show increased activities of one or all of the three arginine (Arg) to NO-converting nitric oxide synthase (NOS) isoforms (iNOS, eNOS, nNOS), but also elevated activities of polyamines-generating and modifying enzymes: arginase I/II, ornithine decarboxylase and spermidine/spermine N¹-acetyltransferase. The degree of stimulation of NO- and polyamine synthesis often correlates with brain tumor malignancy. Excess NO, but also spermine, spermidine and their N¹-acetylated forms, are tumor- and context-dependently involved in angiogenesis, tumor initiation and growth, and resistance to chemo- or radiotherapy. Hypothetically, increased demand for NO and/or polyamines is likely to contribute to Arg auxotrophy of malignant brain tumors, albeit the causal nexus awaits experimental verification.
Double-component diazeniumdiolate derivatives as anti-cancer agents
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Citation Excerpt :
Nitric oxide (NO) is a signaling molecule in a number of human cells. It also involves in many physiological and pathological processes in tumor biology, regulating tumor blood flow, vascular permeability and angiogenesis, controlling the growth, migration and invasion of cancer cells.1–5 Interference of NO signaling might be a promising strategy as a novel cancer treatment.
In this study, we synthesized a series of double-component O²-aryl diazeniumdiolate (DDNO) derivatives, of which each molecule can release up to four nitric oxide molecules. These compounds showed cytotoxic activities to cancer cells, such as human leukemia, breast cancer and lung cancer. Among them, compound 1 (DDNO-1) showed the highest specific activity to human leukemia cells. It induced cell apopotosis and arrest cell cycle of G₂/M phase. The JNK and p38 protein kinases were activated by compound 1 to induce cancer cell apoptosis. Compound 1 also increased pro-apoptotic Bax level, which is a same function compared to a reported NO donor, JS-K. More interestingly, it decreased the level of an anti-apoptotic member Bcl-2, which is an opposite effect compared to JS-K. Compound 1 could be developed as a new anti-cancer agent since it increases the Bax/Bcl-2 ratio to overcome the drug resistance.
Antitumor action of diphenyl diselenide nanocapsules: In vitro assessments and preclinical evidence in an animal model of glioblastoma multiforme
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Citation Excerpt :
It modulates different cellular events dependent on its concentration, such as proliferation, apoptosis, angiogenesis, migration and invasion [46,47]. In gliomas, the NO produced could increase the tumor endothelium permeability, enhancing the delivery of chemotherapeutic drugs [48]. In this sense, our results demonstrated an increase in NO2− levels at the highest concentration tested of NC (PhSe)2 and NC B. Of particular importance, it was already reported that the antitumor effect of substances incorporated into nanocapsules composed of PCL and MCT seems to be associated to an increase in the NO production.
Gliomas are the most aggressive malignant tumors of the central nervous system. The diphenyl diselenide [(PhSe)₂] is an organoselenium compound that has multiple pharmacological properties. Previous reports showed that (PhSe)₂ nanoencapsulation potentiates its in vitro antitumoral action and reduces its toxicity.
In this sense, the current study was designed to further evaluate the (PhSe)₂ antitumoral effect by a set of in vitro techniques using a glioma cell line as well as by an animal model of gliobastoma.
For the in vitro tests, the cell viability, propidium iodide uptake and nitrite levels of rat glioma C6 cells were determined after incubation with free (PhSe)₂ or (PhSe)₂-loaded nanocapsules (NC). The glioblastoma model was induced by implantation of C6 glioma cells in the right striatum of rats. Following, animals were submitted to a repeated intragastric administration treatment with (PhSe)₂ or NC (PhSe)₂ (1 mg/kg/day for 15 days) to assess the possible antitumor effect.
Both compound forms decreased the C6 glioma cells viability without causing any effect in astrocytes cells (healthy control). Importantly, the NC (PhSe)₂ had superior cytotoxic effect than its free form and increased the nitrite content. Independent of the (PhSe)₂ forms, the intragastric treatment reduced brain tumor size and caused neither alteration in the plasma renal and hepatic markers of function nor in the parameters of oxidative balance in brain, liver and kidneys.
The (PhSe)₂ nanoencapsulation improved its cytotoxic effect against C6 glioma cells and both compound forms attenuated the tumor development.
Targeting nitric oxide and NMDA receptor-associated pathways in treatment of high grade glial tumors. Hypotheses for nitro-memantine and nitrones
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Glioblastoma multiforme (GBM) is a devastating brain cancer with no curative treatment. Targeting Nitric Oxide (NO) and glutamatergic pathways may help as adjunctive treatments in GBM. NO at low doses promotes tumorigenesis, while at higher levels (above 300 nM) triggers apoptosis. Gliomas actively secrete high amounts of glutamate which activates EGR signaling and mediates degradation of peritumoral tissues via excitotoxic injury. Memantine inhibits NMDA-subtype of glutamate receptors (NMDARs) and induces autophagic death of glioma cells in vitro and blocks glioma growth in vivo. Nitro-memantines may exert further benefits by limiting NMDAR signaling and by delivery of NO to the areas of excessive NMDAR activity leading NO-accumulation at tumoricidal levels within gliomas. Due to the duality of NO in tumorigenesis, agents which attenuate NO levels may also act beneficial in treatment of GBM. Nitrone compounds including N-tert-Butyl-α-phenylnitrone (PBN) and its disulfonyl-phenyl derivative, OKN-007 suppress free radical formation in experimental cerebral ischemia. OKN-007 failed to show clinical efficacy in stroke, but trials demonstrated its high biosafety in humans including elderly subjects. PBN inhibits the signaling pathways of NF-κB, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX). In animal models of liver cancer and glioblastoma, OKN-007 seemed more efficient than PBN in suppression of cell proliferation, microvascular density and in induction of apoptosis. OKN-007 also inhibits SULF2 enzyme, which promotes tumor growth via versatile pathways. We assume that nitromemantines may be more beneficial concomitant with chemo-radiotherapy while nitrones alone may act useful in suppressing basal tumor growth and angiogenesis.
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Previous studies have shown that serine proteases and Rho-associated kinase contribute to carbon ion radiation-enhanced invasion of the human pancreatic cancer cell line PANC-1. The results presented here show that nitric oxide synthase (NOS) also plays a critical role in this process. Irradiation of PANC-1 cells promoted invasion and production of nitric oxide (NO), which activated the PI3K–AKT signaling pathway, while independently activating RhoA. Inhibition of PI3K, Rho-associated kinase, and serine protease alone or in conjunction with NOS suppressed the radiation-enhanced invasion of PANC-1 cells, suggesting that they could serve as possible targets for the management of tumor metastasis.

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Malignant glioma progression and nitric oxide

Abstract

Section snippets

Malignant gliomas—the problem

Molecular genetics of glioma progression—background information

Nitric oxide and nitric oxide synthase in malignant gliomas

Does nitric oxide affect chemotherapeutic agents?

Summary

Acknowledgments

J. Neurol. Sci.

Int. J. Immunopharmacol.

Lab. Invest.

Cancer Cell

J. Biol. Chem.

Lab. Invest.

Free Radic. Biol. Med.

Gene therapy for high grade gliomas

Expert. Opin. Biol. Ther.

Inhibitors of nitric oxide synthase selectively reduce flow in tumor-associated neovasculature

Br. J. Pharmacol.

Short postoperative survival for glioblastoma patients with a dysfunctional Rb1 pathway in combination with no wild-type PTEN

Clin. Cancer Res.

Predominant expression of mutant EGFR (EGFRvIII) is rare in primary glioblastomas

Brain Pathol.

Amplification and overexpression of MDM2 in primary (de novo) glioblastomas

J. Neuropathol. Exp. Neurol.

Nitric oxide synthase expression and enzymatic activity in human brain tumors

Clin. Neuropathol.

Expression of nitric oxide synthase in human central nervous system tumors

Cancer Res.

PTEN, a unique tumor suppressor gene

Endocr. Relat. Cancer

Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973–1991

J. Neurosurg.

Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production

J. Immunol.

Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails

Proc. Natl. Acad. Sci. U.S.A.

Mechanisms of cell death governed by the balance between nitrosative and oxidative stress

Ann. N. Y. Acad. Sci.

Induction of nitric oxide synthase in rat C6 glioma cells

J. Neurochem.

Analysis of genomic rearrangements associated with EGRFvIII expression suggests involvement of Alu repeat elements

Neurooncology

Microsatellite deletion mapping on chromosome 10q and mutation analysis of MMAC1, FAS, and MXI1 in human glioblastoma multiforme

Int. J. Oncol.

Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures

Proc. Natl. Acad. Sci. U.S.A.

Nitric oxide synthase and cytochrome c oxidase changes in the tumoural and peritumoural cerebral cortex

Acta Neurochir. (Wien.)

Epidermal growth factor receptor gene amplification as a prognostic marker in glioblastoma multiforme: results of a meta-analysis

Oncol. Res.

Amplification of epidermal growth factor receptor gene in gliomas: histopathology and prognosis

J. Neuropathol. Exp. Neurol.

Distinct patterns of deletion on 10p and 10q suggest involvement of multiple tumor suppressor genes in the development of astrocytic gliomas of different malignancy grades

Genes Chromosomes Cancer

Loss of heterozygosity in malignant gliomas involves at least three distinct regions on chromosome 10

Hum. Genet.

Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells

Proc. Natl. Acad. Sci. U.S.A.

The WHO classification of tumors of the nervous system

J. Neuropathol. Exp. Neurol.

Phenotype vs. genotype in the evolution of astrocytic brain tumors

Toxicol. Pathol.