The contribution of N2O3 to the cytotoxicity of the nitric oxide donor DETA/NO: an emerging role for S-nitrosylation

Abstract

The relationship between the biological activity of NO and its chemistry is complex. The objectives of this study were to investigate the influence of oxygen tension on the cytotoxicity of the NO• donor DETA/NO and to determine the effects of oxygen tension on the key RNS (reactive nitrogen species) responsible for any subsequent toxicity. The findings presented in this study indicate that the DETA/NO-mediated cytotoxic effects were enhanced under hypoxic conditions. Further investigations revealed that neither ONOO− (peroxynitrite) nor nitroxyl was generated. Fluorimetric analysis in the presence of scavengers suggest for the first time that another RNS, dinitrogen trioxide may be responsible for the cytotoxicity with DETA/NO. Results showed destabilization of HIF (hypoxia inducible factor)-1α and depletion of GSH levels following the treatment with DETA/NO under hypoxia, which renders cells more susceptible to DETA/NO cytotoxicity, and could account for another mechanism of DETA/NO cytotoxicity under hypoxia. In addition, there was significant accumulation of nuclear p53, which showed that p53 itself might be a target for S-nitrosylation following the treatment with DETA/NO. Both the intrinsic apoptotic pathway and the Fas extrinsic apoptotic pathway were also activated. Finally, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) is another important S-nitrosylated protein that may possibly play a key role in DETA/NO-mediated apoptosis and cytotoxicity. Therefore this study elucidates further mechanisms of DETA/NO mediated cytotoxicity with respect to S-nitrosylation that is emerging as a key player in the signalling and detection of DETA/NO-modified proteins in the tumour microenvironment.

Interactions of a Non‐Thermal Atmospheric Pressure Plasma Effluent with PC‐3 Prostate Cancer Cells

“…Comparing these to the concentrations immediately after exposure (which are 50 ± 3 and 49 ± 21 µM, respectively) we have increases of 40 ± 10 and 47 ± 22 µM, respectively. To give some context, these concentrations are comparable with nitrite concentrations induced over a period of 24 h by moderate concentrations of the NO donor drug DETA/NO, and are approximately double those detected in PC‐3 cells treated with iNOS gene therapy . Furthermore PC‐3 cells undergoing this form of gene therapy have shown significantly reduced viability, which suggests that nitric oxide release by nitrosated proteins, post plasma exposure may at least in part contribute to the apoptosis found to occur in this study.…”

Systemic RALA/iNOS Nanoparticles: A Potent Gene Therapy for Metastatic Breast Cancer Coupled as a Biomarker of Treatment

“…The purpose of the current study was to determine whether cationic RALA-based nanoparticles (NPs) carrying an iNOS transgene had a therapeutic effect in mice bearing MDA-MB-231 (known to be sensitive to the ·NO donor diethylenetriamine (DETA)/NO through generation of dinitrogen trioxide) 20 micrometastases.…”

Nitric oxide: Protein tyrosine phosphorylation and protein S-nitrosylation in cancer

“…[73,74] Apoptosis was related to DETA/NO-induced S-nitrosylation of p53 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in both tumor cell lines. [75,76] These findings illustrate the importance of S-nitrosylation in signaling pathways associated with the induction of apoptosis in cancer cells.…”

“…[73,74] Apoptosis was related to DETA/NO-induced S-nitrosylation of p53 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in both tumor cell lines. [75,76] These findings illustrate the importance of S-nitrosylation in signaling pathways associated with the induction of apoptosis in cancer cells.The anti-adhesive properties of NO demonstrated in the inhibition of platelet aggregation [77] were related to its action on the proteins belonging to the focal adhesion complex resulting in cell death.[78] The anti-adhesive properties of NO include inhibition of cell adhesion and disruption of the interaction between the cell and the extracellular matrix. Its anti-adhesive properties place NO as a potential cause of cell death induced by detachment from a growth permissive surface ("anoikis").…”