NO-Donating NSAIDs, PPAR delta, and Cancer: Does PPAR delta Contribute to Colon Carcinogenesis?

The chemopreventive NO-donating NSAIDs (NO-NSAIDs; NSAIDs with an NO-releasing moiety) modulate PPAR delta and offer the opportunity to revisit the controversial role of PPAR delta in carcinogenesis (several papers report that PPAR delta either promotes or inhibits cancer). This review summarizes the pharmacology of NO-NSAIDs, PPAR delta cancer biology, and the relationship between the two. In particular, a study of the chemopreventive effect of two isomers of NO-aspirin on intestinal neoplasia in Min mice showed that, compared to wild-type controls, PPAR delta is overexpressed in the intestinal mucosa of Min mice; PPAR delta responds to m-and p-NO-ASA proportionally to their antitumor effect (p- > m-). This effect is accompanied by the induction of epithelial cell death, which correlates with the antineoplastic effect of NO-aspirin; and NO-aspirin's effect on PPAR delta is specific (no changes in PPAR alpha or PPAR gamma). Although these data support the notion that PPAR delta promotes intestinal carcinogenesis and its inhibition could be therapeutically useful, more work is needed before a firm conclusion is reached. Copyright (C) 2008 Gerardo G. Mackenzie et al.