Cyclooxygenase-1 (COX-1) and COX-1 Inhibitors in Cancer: A Review of Oncology and Medicinal Chemistry Literature

Abstract

Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE2) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway and to the effects of prostaglandins already known for their ability of affecting the tumor phenotype. A knowledge-based choice of the most appropriate tumor cell models, and a major effort in investigating the COX-1 issue in the more general context of arachidonic acid metabolic network by using the systems biology approaches, should be strongly encouraged.

Ellagic Acid Inhibits Extracellular Acidity-Induced Invasiveness and Expression of COX1, COX2, Snail, Twist 1, and c-myc in Gastric Carcinoma Cells

“…Hence, the inhibitory activity of ellagic acid on both COX1 and COX2 may be associated with the anti-invasive activity in these systems. Although COX1 has long been considered to be constitutively expressed in all tissues and linked to normal physiological functions, not to pathological ones, several recent studies have reported that COX1 can also be upregulated in various pathological conditions and associated with inflammation and cancer [43,44]. Next, we evaluated other genes potentially involved in anti-invasive activity of ellagic acid under acidic conditions.…”

The Multifaceted Role of Heme in Cancer

“…Another possibility is that increased heme synthesis in tumors is intended to support the activity of specific hemoproteins. Cells are equipped with several hemoproteins (69) and for some of them a role in cancer has been reported, including myoglobin (70), tryptophan 2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase 1 and 2 (IDO1/2) (71-73), mitochondrial cytochromes (74, 75), cytochrome P450 (76, 77), and cyclooxygenases (78,79). Studies on lung cancer demonstrated that the amount of oxygen-utilizing hemoproteins, such as cytoglobin, cytochrome c, cytochrome P450 family 1 subfamily B member 1 (CYP1B1) and prostaglandinendoperoxide synthase 2 (COX2) are higher in tumor cells as compared to normal cells and that, at least for cytoglobin and cytochrome c, their levels depend on the rate of heme synthesis and cellular heme content (46).…”

Eicosanoids in carcinogenesis

“…Triggering a fibrotic tissue process by the sulfidopeptide LT stimulated fibroblasts only when simultaneously PG synthesis was suppressed by indomethacin [458]. Detailed knowledge of various pathways with its functional implications is needed and "…metabolic network by using systems biology approaches, should be strongly encouraged" [459]. Furthermore, this needs to include reaction specifity information of regulatory mediators impacting the biological activity of various enzymes and poteins including its dynamic changes [460][461][462][463].…”