A common approach to reduce the adverse effects of NSAIDs such as gastrotoxicity involves rationale structural modification. Recent studies have indicated that addition of a nitric oxide (NO) releasing moiety to common NSAIDs leads to decreased gastrointestinal injury without reduction of the anti-inflammatory and analgesic effects of the parent. Nitroxyl (HNO) also has intriguing properties, such as inhibition of platelet aggregation and glycolysis, via thiol modification of GAPDH, that may be harnessed to enhance the efficacy of NSAIDs as anti-inflammatory or anticancer agents. We have synthesized the first HNO-donating NSAIDs, which like structurally related NO donors show similar anti-inflammatory properties but significantly lower gastrointestinal ulceration than the NSAID alone. Both the HNO and NO donor prodrugs also exhibit higher toxicity to breast cancer cells and significantly reduce tumor growth of breast cancer xenografts in nude mice than the parent NSAID. Detailed analysis has indicted that the cytotoxic and antiproliferative effects of the NO and HNO donor adducts are induced by distinct pathways, which will be described. Overall, HNO-NSAIDs appear to be a unique and promising new class of chemotherapeutic agent.

Nitrogen oxide releasing NSAIDs as anticancer agents

245th National Meeting (2013)

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