NO-donating NSAIDs and cancer: An overview with a note on whether NO is required for their action

Abstract

Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) consist of a conventional NSAID to which an NO-releasing moiety is attached covalently, often via a spacer molecule. NONSAIDs represent an emerging class of compounds with chemopreventive properties against a variety of cancers, demonstrated in preclinical models including cell culture systems and animal tumor models; their potential efficacy in humans has not been assessed. Their mechanism of action appears complex and involves the generation of reactive oxygen species, suppression of microsatellite instability in mismatch repair-deficient cells, and modulation of several signaling cascades that culminate in inhibited cell renewal and enhanced apoptosis. NO, long appreciated to be able to protect from and also promote cancer, is released form NO-NSAIDs and constitutes their defining property. Existing data are consistent with the notion that NO may mediate their anticancer effect. In addition there is evidence that long term administration of NO-donating compounds is not associated with increased incidence of colon cancer. Whether NO release is required for the anticancer effect of NO-NSAIDs has being questioned by recent data indicating that, at least in the case of NO-aspirin, the NO-releasing moiety may serve as a leaving group while the spacer actually being the moiety responsible for its pharmacological action. Regardless of mechanistic issues, these compounds promise to contribute to the control of cancer.

The Evolving Role of Nonsteroidal Anti-Inflammatory Drugs in Colon Cancer Prevention: A Cause for Optimism

“…Nitroaspirin, the most extensively studied, showed significant gastroprotection and efficacy in CRC chemoprevention (Williams et al, 2004). Although it is doubtful whether the release of NO is relevant to either their safety or efficacy when administered systemically (Rigas and Williams, 2008), these compounds displayed interesting pharmacological properties (Rigas, 2007a) but their clinical assessment for CRC chemoprevention was suspended because of potential genotoxicity.…”

Therapeutic Potential of Nitric Oxide-Modified Drugs in Colon Cancer Cells

“…It is known that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the incidence of colon cancer in clinical trials (Coimbra et al, 2009;Rothwell et al, 2010Rothwell et al, , 2011 and that attachment of a NO moiety to the parent NSAIDs reduced gastrotoxicity and increased their antitumor properties owing to an intrinsic feature of this reactive molecule to induce tumor cell death (Yeh et al, 2004;Gao et al, 2005;Rigas and Williams, 2008).…”

Evaluation of antioxidative effects of twelve 3-substituted-5,5-diphenylhydantoins on human colon cancer cell line HCT-116

“…This can be partly explained by the fact that NO · has a half-life of only several seconds in an environment rich in superoxide anion radicals; surrounded by low levels of superoxide anion radicals, NO · has much greater stability (Valko et al, 2006). Nitric oxide is an important signaling molecule in numerous physiological and pathological conditions (Liu et al, 2003;Rigas and Williams, 2008). NO · has been reported to have antitumor activities as well as protumor properties.…”