COX-derived prostanoid pathways in gastrointestinal cancer development and progression : novel targets for prevention and intervention

Cathcart, Mary Clare, O'Byrne, Kenneth J., Reynolds, John V., O'Sullivan, Jacintha, & Pidgeon, Graham P. (2012) COX-derived prostanoid pathways in gastrointestinal cancer development and progression : novel targets for prevention and intervention. Biochimica et Biophysica Acta - Reviews on Cancer, 1825(1), pp. 49-63.

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Abstract

Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE 2, which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA 2 in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD 2 and its metabolite 15d-PGJ2, PGF 1α and PGI 2. Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity.A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field. © 2011 Elsevier B.V.

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ID Code: 64854
Item Type: Journal Article
Refereed: Yes
Additional URLs:
Keywords: Cancer, Colorectal, Cyclooxygenases, Esophagus, Prostanoids, Stomach, 15 hydroxyprostaglandin dehydrogenase, acetylsalicylic acid, arachidonic acid, celecoxib, curcumin, cyclooxygenase 1, cyclooxygenase 2, cyclooxygenase 2 inhibitor, nonsteroid antiinflammatory agent, peroxisome proliferator activated receptor gamma, prostacyclin, prostaglandin D2, prostaglandin E receptor, prostaglandin E synthase, prostaglandin E2, prostaglandin F2 alpha, prostaglandin synthase, prostanoid, rofecoxib, thromboxane A2, Barrett esophagus, cancer growth, cancer incidence, cancer prevention, carcinogenesis, cardiotoxicity, chemoprophylaxis, colon cancer, colorectal cancer, digestive system cancer, drug mechanism, drug targeting, enzyme metabolism, esophageal adenocarcinoma, esophagus cancer, gastrointestinal hemorrhage, human, kidney disease, malignant transformation, nonhuman, priority journal, protein expression, protein function, review, signal transduction, stomach cancer, Cyclooxygenase 2 Inhibitors, Disease Progression, Gastrointestinal Neoplasms, Molecular Targeted Therapy, Prostaglandin-Endoperoxide Synthases, Prostaglandins, Prostaglandins E
DOI: 10.1016/j.bbcan.2011.09.004
ISSN: 0304-419X
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 Elsevier BV
Deposited On: 27 Nov 2013 07:42
Last Modified: 29 Nov 2013 04:42

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