NO-NSAIDs

Chang SY, Howden CW. Is no NSAID a good NSAID Approaches to NSAID-associated upper gastrointestinal disease. Curr Gastroenterol Rep. 2004 6 447-453. 

NONSTEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) AND THE DEVELOPMENT OF NO-NSAIDS... 

New classes of NSAIDs that release NO, called NO-NSAIDs, have been discovered and early clinical evidences suggests that these compounds could be safe and effective alternatives to conventional NSAIDs. These agents comprise two classes of compounds, one that contains a nitrate ester functionality (48) and one that contains an S-nitrosothiol functionality (49). 

NO-NSAIDs have a profound effect on colon cancer kinetics, inhibiting both proliferation and enhancing cell death. This is accompanied by a dramatic effect on cell cycle, arresting the progression of the cell to the S phase (Williams et al. 2001). Moreover, NO-NSAIDs affect several important pathways and these effects may contribute to their chemopreventive effect they include the eicosanoid pathway, the NO pathway, and the signaling system involving NF-kB pathway (Fig. 4.1). 

Fig. 4.1 Effects of NO-NSAIDs on COX and NOS nuclear factor kB (NF-kB) pathways. NO-NSAIDs inhibit proliferation and induce cell death reducing tumor mass...

Dunlap, T, Abdul-Hay, S.O., Chandrasena, R.E., Hagos, G.K., Sinha, V., Wang, Z., Wang, H., and Thatcher, G.R. (2008). Nitrates and no-nsaids in cancer chemoprevention and therapy In vitro evidence querying the no donor functionality. Nitric Oxide 19, 115-124. 

Rosetti, M., Tesei, A., Ulivi, R, Fabbri, F, Vannini, I., Brigliadori, G., Amadori, D., Bolla, M., and Zoli, W. (2006). Molecular characterization of cytotoxic and resistance mechanisms induced by ncx 4040, a novel no-nsaid, in pancreatic cancer cell lines. Apoptosis 11, 1321-1330. 

Keywords Cancer biology Cancer chemoprevention Furoxans Nitric oxide releasing molecule (NORM) NONOate NO-NSAID Quinone methide... 

NO-NSAIDs were conceived as prodrugs to utilize NO release for side effect attenuation. However, growing evidence for the chemotherapeutic and chemo-preventive attributes of NO release has led researchers to attempt to harness these properties. The NO releaser in these hybrid NORMs is, in the parlance of chemotherapeutics, a drug warhead. Hybrid NORMs have come to dominate the field therefore, before reviewing the individual classes of NORMs, it is important to examine the concept of the hybrid NORM. 

The comparison of a hybrid NORM drug versus a comparable combination therapy has rarely been studied in vivo for example, a cocktail of NSAID + ISDN (isosorbide dinitrate) compared to an NO-NSAID. In one case where a comparison was made with NCX 4016 the cocktail was equi-efficacious (Brzozowska et al. 2004). In several hybrid NORM designs, such as JS-K and GT-094, bioactivation to release the warhead bioactivity is contingent upon the presence of the linker (Shami et al. 2003 Zavorin et al. 2001). 

Drugs that are FDA approved (classical nitrates, nitrites, molsidomine) or have completed early phase clinical trials in other indications (NO-NSAIDS) have, at present, the best prospects for clinical use. The in vitro genotoxicity of several examples of most classes of NORMs is a dampener to use in cancer chemoprevention, even in the absence of any evidence of carcinogenicity. 

The NO-ASA family of NO-NSAIDs, notably NCX 4016 [Fig. 20.2(a)] and NCX 4040 [Fig. 20.2(b)], has been extensively researched. These two isomeric hybrid NORMS differ only in the snbstitution of the linker group. Hulsman et al. was the first to comment that in NCX-4040 the presnmed invisible linker is in fact solely responsible for the anti-tumor effect of the molecule and that both the NO-release warhead and the ASA are passive bystanders (Hulsman, Medema et al. 2007). The Unker warhead moiety is efficiently bioactivated to a quinone methide thiophiUc electrophile, in simile with much earUer literature reports (Myers and Widlanski 1993). Molecules in which the nitrate group of NO-ASA was replaced by a comparably good leaving group (termed X-ASA Fig. 20.12) showed very similar properties in vitro with respect to activity (1) cytotoxic/genotoxic (2) antiproliferative (3) chemopreventive (ARE activation - phase 11 enzyme induction) and (4) the anti-inflammatory (Dunlap et al. 2(X)7, 2008). 

Williams et al. (2001) NO-NSAIDS Human colon cancer (HT2) Proliferation (PCNA) apoptosis (morphology and flow cytometry) Lowest IC50 1 [xM (NCX 4040) ... 

Kashfi et al. (2002) NO-NSAIDS Human pancreatic (PaCa-2), prostate (LNCap), lung (A549), colon (HT-29 and HCT-15) and tongue (SCC-25) cancers Cell growth curves Lowest IC50 1 p-M (NO aspirin) ... 

Royle et al. (2004) NO-NSAIDS Human prostate (LNCap and PC-3) Cell viability (MTT) and apoptosis (TUNEL) <80% growth inhibition by NO aspirin (NCX 4060) and <90% apoptotic cells ... 

Gao et al. (2005) NO-NSAID Human colon adenocarcinoma (SW48, HCT-15 andLoVo) Cell growth (luciferase assay) inhibition Lowest IC50 34 p.M (NCX 4040 for 48 h) ... 

Tessei et al. (2005) NO-NSAIDS Human colon (LoVo, LoVo Dx,WiDrandLRWZ) Cell growth (SRB assay) and apoptosis (TUNEL) Lowest IC50 10 p,M (NCX 4040) Human colon cancer cell lines (LoVo, LoVo Dx, WiDr) 40% reduction in tumour weight after NCX 4040 (10 mg/kg) 5 times/week for 6 weeks... 

Jannsens et al. (1998) NO-NSAIDS, SNAP or iNOS induced by IFN-y Mouse mammary carcinoma (EMT-6) Clonogenic survival SER 2.4 in 10 units/ml lEN-y or in 300 p,M PAPA-NO ... 

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