Nonsteroidal anti-inflammatory drugs (NSAIDs) have emerged as significant chemopreventative agents; however, their limited efficacy and appreciable side effects have motivated investigation of modified NSAIDs to enhance their efficacy and/or decrease their side effects. The chemopreventative mechanisms of NSAIDs do not represent the dominant mechanism and are not sufficient to explain their efficacy. Sun et al. characterized several structurally distinct phospho-NSAIDs, both in vitro and in vivo, to arrive at a potentially unifying mechanistic theme of induction of oxidative stress. Phospho-NSAIDs increased levels of reactive oxygen and nitrogen species and decreased cellular antioxidant defense mechanisms (i.e., the thioredoxin system and glutathione). In tumor xenografts, phospho-NSAIDs suppressed tumor growth through induction of apoptosis, which correlated with the production of F2-iosprotane levels, a marker of oxidative stress. Induction of apoptosis was only observed in xenograft and not normal tissues, such as colonic mucosa, and increases in F2-isoprostane levels were seen only in tumor-bearing animals. This study underscores the potentially critical role of the induction of oxidative stress in the therapeutic effect of phospho-NSAIDs and indicates that pathways leading to oxidative stress may be useful targets for anticancer strategies.
See article at J Pharmacol Exp Ther 2011, 338:775–783.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics