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Effects of the nitric oxide donor JS-K on the blood-tumor barrier and on orthotopic U87 rat gliomas assessed by MRI.

ABSTRACT: Nitric oxide (NO) released from NO donors can be cytotoxic in tumor cells and can enhance the transport of drugs into brain tumors by altering blood-tumor barrier permeability. The NO donor JS-K [O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] releases NO upon enzymatic activation selectively in cells overexpressing glutathione-S-transferases (GSTs) such as gliomas. Thus, JS-K-dependent NO effects - especially on cell viability and vascular permeability - were investigated in U87 glioma cells in vitro and in an orthotopic U87 xenograft model in vivo by magnetic resonance imaging (MRI). In vitro experiments showed dose-dependent antiproliferative and cytotoxic effects in U87 cells. In addition, treatment of U87 cells with JS-K resulted in a dose-dependent activation of soluble guanylate cyclase and intracellular accumulation of cyclic guanosine monophosphate (cGMP) which was irreversibly inhibited by the selective inhibitor of soluble guanylate cyclase ODQ (1H-[1,2,4]oxadiazolo(4,3a)quinoxaline-1-one). Using dynamic contrast enhanced MRI (DCE-MRI) as a minimally invasive technique, we demonstrated for the first time a significant increase in the DCE-MRI read-out initial area under the concentration curve (iAUC60) indicating an acute increase in blood-tumor barrier permeability after i.v. treatment with JS-K. Repeated MR imaging of animals with intracranial U87 gliomas under treatment with JS-K (3.5 ?mol/kg JS-K 3×/week) and of untreated controls on day 12 and 19 after tumor inoculation revealed no significant changes in tumor growth, edema formation or tumor perfusion. Immunohistochemical workup of the brains showed a significant antiproliferative effect of JS-K in the gliomas. Taken together, in vitro and in vivo data suggest that JS-K has antiproliferative effects in U87 gliomas and opens the blood-tumor barrier by activation of the NO/cGMP signaling pathway. This might be a novel approach to facilitate entry of therapeutic drugs into brain tumors. DCE-MRI is a non-invasive, repeatable imaging modality to monitor biological effects of NO donors and other experimental therapeutics in intracranial tumor models.

SUBMITTER: Weidensteiner C

PROVIDER: S-EPMC3617040 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Effects of the nitric oxide donor JS-K on the blood-tumor barrier and on orthotopic U87 rat gliomas assessed by MRI.

Weidensteiner Claudia C Reichardt Wilfried W Shami Paul J PJ Saavedra Joseph E JE Keefer Larry K LK Baumer Brunhilde B Werres Anna A Jasinski Robert R Osterberg Nadja N Weyerbrock Astrid A

Nitric oxide : biology and chemistry 20130128

Nitric oxide (NO) released from NO donors can be cytotoxic in tumor cells and can enhance the transport of drugs into brain tumors by altering blood-tumor barrier permeability. The NO donor JS-K [O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] releases NO upon enzymatic activation selectively in cells overexpressing glutathione-S-transferases (GSTs) such as gliomas. Thus, JS-K-dependent NO effects - especially on cell viability and vascular permeability - w ...[more]

PMID: 23370169

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Project description:Airway epithelium forms a physical barrier that protects the lung from the entrance of inhaled allergens, irritants, or microorganisms. This epithelial structure is maintained by tight junctions, adherens junctions and desmosomes that prevent the diffusion of soluble mediators or proteins between apical and basolateral cell surfaces. This apical junctional complex also participates in several signaling pathways involved in gene expression, cell proliferation and cell differentiation. In addition, the airway epithelium can produce chemokines and cytokines that trigger the activation of the immune response. Disruption of this complex by some inflammatory, profibrotic, and carcinogens agents can provoke epithelial barrier dysfunction that not only contributes to an increase of viral and bacterial infection, but also alters the normal function of epithelial cells provoking several lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF) or lung cancer, among others. While nitric oxide (NO) molecular pathway has been linked with endothelial function, less is known about the role of the NO system on the bronchial epithelium and airway epithelial cells function in physiological and different pathologic scenarios. Several data indicate that the fraction of exhaled nitric oxide (FENO) is altered in lung diseases such as asthma, COPD, lung fibrosis, and cancer among others, and that reactive oxygen species mediate uncoupling NO to promote the increase of peroxynitrite levels, thus inducing bronchial epithelial barrier dysfunction. Furthermore, iNOS and the intracellular pathway sGC-cGMP-PKG are dysregulated in bronchial epithelial cells from patients with lung inflammation, fibrosis, and malignancies which represents an attractive drug molecular target. In this review we describe in detail current knowledge of the effect of NOS-NO-GC-cGMP-PKG pathway activation and disruption in bronchial epithelial cells barrier integrity and its contribution in different lung diseases, focusing on bronchial epithelial cell permeability, inflammation, transformation, migration, apoptosis/necrosis, and proliferation, as well as the specific NO molecular pathways involved.

Project description:Nitric oxide (NO) releasing polymers have been widely applied as biomaterials for a variety of biomedical implants and devices. However, the chemical leaching of NO donors and their byproduct species is almost always observed during the application of polymers doped with NO donors, unless the donor is covalently linked to the polymer. Herein, we report the first NO releasing poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) fluorinated copolymer prepared by incorporating a fluorinated S-nitrosothiol as the NO donor. Under physiological conditions, the resulting polymeric films can release NO for 16?days. Importantly, due to both fluorine-fluorine and electrostatic charge interactions between the fluorinated NO donor and the PVDF-HFP copolymer, the total chemical leaching of the fluorinated NO donor and its disulfide product after 9?day was only 0.6% (mol%) of the initial amount of NO donor loaded into the film. These new NO release PVDF-HFP films exhibit antimicrobial and anti-biofilm activities against both Gram positive S. aureus and Gram negative P. aeruginosa strains. The NO-releasing PVDF-HFP polymer can also be coated on Teflon tubing to release NO under physiological conditions for extended time periods. This NO-releasing PVDF-HFP copolymer with greatly reduced chemical leaching could help enhance the biocompatibility and antimicrobial activity of various biomedical devices. STATEMENT OF SIGNIFICANCE: Fluoropolymers have been widely used in creating various biomedical implants and devices. However, nitric oxide (NO) release fluoropolymers have not been well studied to date. Additionally, in the application of biomaterials doped with NO donors, a significant amount of NO donors and their byproducts almost always leach into aqueous environment. We now report an NO releasing poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) fluoropolymer by incorporating a new fluorinated S-nitrosothiol. The NO release can last for 16?days under physiological conditions. The total chemical leaching was determined to be only 0.6?mol% of the initial S-nitrosothiol loaded. As expected, significant antimicrobial/anti-biofilm activities of the NO release PVDF-HFP film were observed against Gram positive S. aureus and Gram negative P. aeruginosa bacterial strains.

Dataset Information

Effects of the nitric oxide donor JS-K on the blood-tumor barrier and on orthotopic U87 rat gliomas assessed by MRI.

Publications

Effects of the nitric oxide donor JS-K on the blood-tumor barrier and on orthotopic U87 rat gliomas assessed by MRI.

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