Gamma-glutamyl transpeptidase overexpression and an interorgan flow of GSH, by increasing cysteine availability for tumor GSH synthesis, promote metastatic growth.

The mechanism of NO- and H2O2-induced tumor cytotoxicity has been examined during murine B16 melanoma (B16M) adhesion to the vascular endothelium. H2O2

was AZD7762 clinical trial not cytotoxic in the absence of NO. But, NO-induced tumor cytotoxicity was increased by H2O2 due to the formation of potent oxidants, likely OH and -OONO radicals, via a trace metal-dependent process. B16M cells with high GSH content were more resistant to NO and H2O2, Cancer cell survivors showed higher Bcl-2 and GSH levels. Metastatic invaders, after surviving attack by tissue macrophages, may further enhance their resistance. (C) 2008 Elsevier Inc. All rights reserved.”
“Properties of the NO-ASA family of No-donating NSAIDs (NO-NSAIDs), notably NCX 4016 (mNO-ASA) and NCX 4040 (pNO-ASA), reported in more than one hundred publications, have included positive preclinical

Rigosertib datasheet data in cancer chemoprevention and therapy. Evidence is presented that the antiproliferative, the chemopreventive (antioxidant/electrophile response element (ARE) activation), and the anti-inflammatory activity of NO-ASA in cell cultures is replicated by X-ASA derivatives that are incapable of acting as NO donors. pBr-ASA and mBr-ASA are conisogenic with NO-ASA, but are not NO donors. The biological activity of pNO-ASA is replicated by pBr-ASA; and both pNO-ASA and pBr-ASA are bioactivated to the same quinone methide electrophile. The biological activity of mNO-ASA is replicated by mBr-ASA: mNO-ASA and mBr-ASA are bioactivated to different benzyl electrophiles. The observed activity is likely initiated by trapping of thiol biomolecules by the quinone and benzyl electrophiles, leading to depletion of GSH and modification of Cys-containing sensor proteins. Whereas all NO-NSAIDs containing the same structural “”linker”" as either NCX 4040 and NCX 4016 are anticipated

to possess activity resulting from bioactivation to electrophilic metabolites, this expectation does not extend to other linker structures. Nitrates require metabolic bioactivation to liberate NO bioactivity, which is often poorly replicated in vitro, and NO bioactivity provided by NO-NSAIDs in vivo provides proven therapeutic benefits in mitigation of NSAID gastrotoxicity. The in vivo properties of X-ASA drugs await discovery. (C) 2008 Elsevier Inc. All rights reserved.”
“Nitric oxide (NO) is a multifunctional regulator, critical to various biochemical processes, including inflammation, vasodilatation, intra- and intercellular signaling, apoptosis, and carcinogenesis. In particular, recent studies have indicated the association between elevated NO production and neoplastic cell transformation, suggesting procarcinogenic effects of NO.