Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.

Cyclooxygenase Isozymes: The Biology of Prostaglandin Synthesis and Inhibition

Colorectal cancer (CRC) is a heterogeneous disease, including at least three major forms: hereditary, sporadic and colitis-associated CRC. A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet and lifestyle are the risk factors for CRC. As elevated cyclooxygenase-2 (COX-2) expression was found in most CRC tissue and is associated with worse survival among CRC patients, investigators have sought to evaluate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors (COXIBs) on CRC. The epidemiological studies, clinical trials and animal experiments indicate that NSAIDs are among the most promising chemopreventive agents for this disease. NSAIDs exert their anti-inflammatory and antitumor effects primarily by reducing prostaglandin production by inhibition of COX-2 activity. In this review, we highlight breakthroughs in our understanding of the roles of COX-2 in CRC and inflammatory bowel disease. These recent data provide a rationale for re-evaluating COX-2 as both the prognostic and the predictive marker in a wide variety of malignancies and for renewing the interest in evaluating relative benefits and risk of COXIBs in appropriately selected patients for cancer prevention and treatment.

The Role of COX-2 in Intestinal Inflammation and Colorectal Cancer

https://www.cell.com/cell-metabolism/pdf/S1550-4131(13)00103-4.pdf

The Endocannabinoid System in Energy Homeostasis and the Etiopathology of Metabolic Disorders

Based upon evidence that the therapeutic properties of Cannabis preparations are not solely dependent upon the presence of Δ9-tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. Here, we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent pre-clinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action and thus appear very unlikely to produce unwanted CNS effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low-affinity CB1 ligand that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.12944

Are cannabidiol and Δ9‐tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review

Prostanoids are cyclic, oxygenated products of ω3 and ω6 20- and 22-carbon essential fatty acids (FAs) that are formed enzymatically through “cyclooxygenases”. Prostaglandin endoperoxide synthases -1 and -2 (PGHS-1 and -2)a, which are also known as cyclooxygenases -1 and -2 (COX-1 and -2), catalyze the committed step in the biosynthesis of prostanoids (Figure 1). These compounds include what are sometimes referred to as the “classical” prostaglandins (PGs) PGD, PGE, and PGF as well as prostacyclins denoted as PGI's and the thromboxanes abbreviated Tx's; monohydroxy acids can also be formed via PGHSs, but information on the possible physiologic importance of such compounds is incomplete.1-3 The most abundant prostanoids are the “2-series” compounds (e.g. PGE2) that are formed from arachidonic acid (AA; 5Z, 8Z, 11Z, 14Z- eicosatetraenoic acid; 20:4 ω6; Figure 1). The “2” denotes the number of carbon-carbon double bonds in the product.



Figure 1

Biosynthetic pathway for the formation of prostanoids



PGHSs catalyze two distinct reactions that occur at physically distinct but functionally interacting sites. The cyclooxygenase (COX) reaction is a bis-oxygenation in which two O2 molecules are inserted into the carbon backbone of AA to yield PGG2 (Figure 1). The peroxidase (POX) reaction is a transformation in which the 15-hydroperoxyl group of PGG2 undergoes a net two electron reduction to PGH2 plus water. The POX reaction is important in the enzyme mechanism, but other peroxidases such as glutathione peroxidase may contribute importantly to the reduction of PGG2 to PGH2 in vivo.

PGH2 is thought not to accumulate in cells but rather to be converted quickly to what are considered the biologically relevant, downstream products. There are specific synthases involved in forming PGD2, PGE2, PGF2α, PGI2 and TxA2 from PGH2. Except for the case of PGF2α, which is formed by a two electron reduction of PGH2, these enzymes catalyze non-oxidative rearrangements. Finally, there is a PGH 19-hydoxylase that converts PGHs to their corresponding 19-hydroxy derivatives which themselves are substrates for PGE synthase(s). There are one or more specific G protein-linked receptors for each prostanoid, and in some cases prostanoids may also act through nuclear peroxisome proliferator activated receptors.

AA and other 20- and 22-carbon, highly unsaturated FAs are found esterified at the sn2 position of glycerophospholipids. Basal prostanoid formation generally occurs at a low rate relative to stimulated formation. A major factor limiting prostanoid formation is AA availability, which is controlled through the net rates of deacylation and reacylation of glycerophospholipids. Prostanoid formation is enhanced when phospholipase A2 (PLA2) activity is increased, and thus PLA2s play a substrate-limiting role in regulating prostanoid biosynthesis. Although reacylation may also be important, its possible role in regulating prostanoid biosynthesis is largely unexplored.

In this chapter we review the biochemistry and the biochemical pharmacology of the enzymes involved in converting AA to various prostanoid products. These enzymes include PGHS-1, PGHS-2, hematopoietic PGD synthase (H-PGDS), lipocalin-type PGD synthase (L-PGDS), microsomal PGE synthase-1 (mPGES-1), microsomal PGE synthase-2 (mPGES-2), cytosolic PGE synthase (cPGES), PGF synthase (PGFS), PGI synthase (PGIS) and TXA synthase (TXAS). The PLA2s involved in mobilizing AA and the receptors through which prostanoids function are surveyed in other chapters of this volume.

Enzymes of the Cyclooxygenase Pathways of Prostanoid Biosynthesis

Metabolism of the Endocannabinoids, 2-Arachidonylglycerol and Anandamide, into Prostaglandin, Thromboxane, and Prostacyclin Glycerol Esters and Ethanolamides

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Metabolism of the Endocannabinoids, 2-Arachidonylglycerol and Anandamide, into Prostaglandin, Thromboxane, and Prostacyclin Glycerol Esters and Ethanolamides