Cyclopentenone prostaglandins: New insights on biological activities and cellular targets

The cyclopentenone prostaglandins PGA(2):, PGA(1), and PGJ(2) are formed by dehydration within the cyclopentane ring of PGE(2), PGE(1), and PGD(2), PG J(2) is metabolized further to yield Delta (12)-PGJ(2) and 15-deoxy-Delta ( 12,14)-PGJ(2) (15d-PGJ(2)). Various compounds within the cyclopentenone pro staglandin family possess potent anti-inflammatory, anti-neoplastic, and an ti-viral activity. Most actions of the cyclopentenone prostaglandins do not appear to be mediated by binding to G-protein coupled prostanoid receptors . Rather, the bioactivity of these compounds results from their interaction with other cellular target proteins. 15-deoxy-Delta (12,14)-PGJ(2) is a hi gh affinity ligand for the nuclear receptor PPAR gamma and modulates gene t ranscription by binding to this receptor, Other activities of the cyclopent enone prostaglandins are mediated by the reactive alpha,beta -unsaturated c arbonyl group located in the cyclopentenone ring. The transcription factor NF-kappaB and its activating kinase are key targets for the anti-inflammato ry activity of 15d-PGJ(2), which inhibits NF-kappaB-mediated transcriptiona l activation by PPAR gamma -dependent and independent molecular mechanisms. Other cyclopentenone prostaglandins, such as Delta (7)-PGA(1) and Delta (1 2)-PGJ(2), have strong anti-tumor activity. These compounds induce cell cyc le arrest or apoptosis of tumor cells depending on the cell type and treatm ent conditions. We review here recent progress in understanding the mechani sms of action of the cyclopentenone prostaglandins and their possible use a s therapeutic agents, (C) 2001 John Wiley & Sons, Inc.