Mechanisms leading to COX-2 expression and COX-2 induced tumorigenesis: topical therapeutic strategies targeting COX-2 expression and activity.
The biological role of COX-2, the inducible form of cyclooxygenase, is to convert arachidonic acid into prostaglandins (PGs) and thromboxanes (TXs). Overexpressed in many tumors, COX-2 plays a crucial role in cancer through synthesis of PGs which stimulate PGs receptors with subsequent enhancement of cellular proliferation, promotion of angiogenesis, inhibition of apoptosis, stimulation of invasion/motility, and suppression of immune responses. Depending on the tissue specificity and the cell type, several signaling pathways (Kinases, Rho, cGMP and Wnt), and transcription factors such as AP1, NFAT or NF-kappaB, are involved in COX-2 expression. In this review, we will describe mechanisms required by COX-2 metabolites to promote cancer development, and also the signaling pathways leading to COX-2 expression. In order to counteract the negative effects of COX-2 in cancerogenesis, chemicals interfering with COX-2 activity and expression were designed. We will give in the last part of this article, an overview of these potent chemicals interfering with the COX-2 signaling pathways involved in its expression or with its activity.
Telliez
Aurélie
A
Institut de Chimie Pharmaceutique Albert Lespagnol, EA 2692, 3 rue du Professeur Laguesse, BP 83, F-59006 Lille, France.
Furman
Christophe
C
Pommery
Nicole
N
Hénichart
Jean-Pierre
JP
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000502:physiology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000502:physiology; D018450:Disease Progression; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology; D047492:Peroxisome Proliferator-Activated Receptors / Q000037:antagonists & inhibitors; D011453:Prostaglandins / Q000096:biosynthesis / Q000502:physiology; D011982:Receptors, Prostaglandin / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D009363:Neoplasm Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D011453:Prostaglandins; D011982:Receptors, Prostaglandin; D051546:Cyclooxygenase 2; D015232:Dinoprostone