Nitrates and NO-NSAIDs in cancer chemoprevention and therapy: In vitro evidence querying the NO donor functionality

Abstract

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 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 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.

NO‐sulindac inhibits the hypoxia response of PC‐3 prostate cancer cells via the Akt signalling pathway

“…40 The low levels of nitrite released by NO-sulindac concur with these predictions, it may be that the NO…”

NCX 4040, a Nitric Oxide-Donating Aspirin, Exerts Anti-Inflammatory Effects through Inhibition of IκB-α Degradation in Human Monocytes

“…The two positional isomers differ in their metabolism in vivo, which likely correlates with their differential effects on cancer cell growth (15). In fact, NCX 4040, but not NCX 4016, was found to have antitumor activities (19,20). It was recently found that neither aspirin nor NO contributes to the antitumor effect of NCX 4040, which, in contrast, seems to be due to the quinone methide formed after carboxylic ester hydrolysis (21,22).…”

The antineoplastic effect of nitric oxide-donating acetylsalicylic acid (NO-ASA) in chronic lymphocytic leukemia (CLL) cells is highly dependent on its positional isomerism

“…Subsequently, a crucial role for aromatic resonance interaction can be suggested. In general it has been speculated that a major requirement for the cytotoxic effect is the presence of an aromatic ring substituted with both a masked phenolic group and a para-methylene group allowing the generation of a quinone methide [Dunlap et al 2009[Dunlap et al , 2007Hulsman et al 2007]. Owing to the structural position of the ÀONO 2 group, the meta-isomer is not capable of generating such a toxic methide.…”