Cyclooxygenases in cancer: progress and perspective.

Since their discovery in the mid 1930s as potent bioactive compounds in human semen (1), prostaglandins and their relatives have fascinated several generations of scientists. Prostanoids, as they are known today, are a specific class of bioactive mediators generated via initial actions of cyclooxygenase. They are part of a much larger group of compounds, the eicosanoids, which, although ubiquitous as a group, are produced by a variety of cell type–, tissue-, and species-specific biosynthetic pathways. The eicosanoid family encompasses thromboxanes, prostacyclins, leukotrienes, hydroxyeicosatetraenoic acids (HETEs), epoxyeicosatrienic acids (EETs), lipoxins, and isoprostanes, the last of which can be generated by nonenzymatic oxidative mechanisms and may serve as markers of oxidative stress in humans. Each class of enzymatically produced eicosanoids governs a specific set of functions and is thought to serve as a mediator or autacoid, acting within a local microenvironment to orchestrate key cellular responses. A goal of this Perspective is to provide a succinct view of salient findings and historical background in this area necessary for the reader to evaluate the potential importance of the newly uncovered “unorthodox” routes (2–4) initiated via cyclooxygenase (for detailed reviews see refs. 5–7).

Structures of the first six prostaglandins (PGs) were established by 1962, before their individual biosynthetic pathways were studied. These compounds are synthesized in vivo through what can now be regarded as the “orthodox” cyclooxygenase pathways, which came to light largely through the work of Sune Bergstrom, who led a team then based at the Karolinska Institutet in Stockholm. Bergstrom stated in his 1982 Nobel lecture that, following the structural assignments of the six PGs, “These 20-carbon prostaglandins have cis–double bonds located as in certain essential fatty acids, when counting from the carboxyl. This made us suspect that these naturally occurring acids might be precursors” (see ref. 5 and references within). Indeed, evidence obtained with isotopically labeled 20-carbon fatty acids incubated with sheep vesicular glands, an abundant source of PGs, confirmed this assumption. More importantly, this finding shattered a dogma of the time that held that fatty acids played only structural roles in cells, thus opening the way for discovery of the many other important bioactive fatty acid–derived products. These compounds fall into several distinct classes and include the leukotrienes (LTs) and the lipoxins (lipoxygenase interaction products or LXs; see ref. 9). Eicosanoids play pivotal roles in parturition, inflammation, hemodynamics, and renal function, and our appreciation of their bioimpact and relevance to human diseases is still evolving. Here, we focus on newly uncovered pathways, involving either the cyclooxygenases (COXs) or nonenzymatic chemical transformations, that lead to the formation of bioactive prostanoids and of previously unknown lipid mediators produced by COX-2.

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Unorthodox routes to prostanoid formation: new twists in cyclooxygenase-initiated pathways

The multicomponent analysis of estrogens in urine by ion exchange chromatography and GC-MS--I. Quantitation of estrogens after initial hydrolysis of conjugates.

The major initial steps in the degradation of the prostaglandins are the oxidation of the secondary alcohol group at C-15 and the reduction of the Δ13 double bond (for a recent review, see 1). The two enzymes that catalyze these reactions are 15-hydroxyprosta-noate dehydrogenase and Δl3 reductase. The metabolites formed by these reactions, the 15-keto and the 15-keto-13,14-dihydro compounds, have considerably lower biologic activities than the parent prostaglandins; thus, the dehydrogenation has been considered a key step in the biological inactivation of prostaglandins. To a certain extent, reduction of the formed keto group to a hydroxyl may also take place. The biological activity of the resulting compound, the 13,14-dihydro prostaglandin, may be considerable in certain systems.

Metabolism of Prostaglandins

Human seminal plasma has potent anti-inflammatory properties which are thought to confer a survival advantage to the spermatozoa within the hostile female genital tract. In contrast, a profound pro-inflammatory leukocytosis has been observed post-coitus in animals and humans. Whether components of seminal plasma are involved in initiating this leukocytic reaction is not known. This study investigated the effect of human seminal plasma, a seminal plasma fraction and its principal constituent prostaglandins, prostaglandin E2 (PGE2) and 19-hydroxy PGE, on the release of the pro-inflammatory neutrophil chemotactic factor interleukin8 (IL-8) and the anti-inflammatory cytokines interleukin-10 (IL-10) and secretory leukocyte protease inhibitor (SLPI). The tissues studied were non-pregnant cervical explants, peripheral blood and the monocyte cell line U937. Seminal plasma fraction (SPF) significantly (P < 0.05) stimulated release of IL-8 and inhibited release of SLPI from non-pregnant cervical explants. SPF, PGE2 and 19-hydroxy PGE significantly (P < 0.005) stimulated IL-8 release from peripheral blood and U937 cells. 19-hydroxy PGE was significantly (P < 0.005) more effective than PGE2 in stimulating IL-8 release. Seminal plasma, SPF and PGE2 significantly (P < 0.05) stimulated IL-10 release from U937 cells. 19-hydroxy PGE stimulated IL-10 release from U937 cells but this failed to reach significance. Release of IL-10 by cervical explants and SLPI by peripheral blood and U937 cells were below the detection limit of the assays employed. We suggest that the anti- and pro-inflammatory immune responses which seminal plasma induces might act in combination initially to promote sperm survival and then to facilitate their removal from the female genital tract.

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Seminal plasma components stimulate interleukin-8 and interleukin-10 release.

ALMOST 30 years after the initial discovery of the prostaglandins, Bergstrom et al., succeeded in isolating and identifying prostaglandins (PGs) E1, E2, F1α and F2α from sources including human semen1. It was subsequently claimed2 that the 19-hydroxy derivatives of prostaglandins A and B were also present. These compounds were later found at an average concentration of 40 µg ml−1 (ref. 3), In a detailed study of semen PGs we have used a new approach for the measurement of the E prostaglandins, which involves protecting the unstable β-ketol system by oximation in the unextracted semen, thus ensuring minimal degradation to the A or B series. Using this technique we found that the levels of 19-hydroxy derivatives of PGA and PGB are relatively low whereas two new PGs, later identified as 11α,15,19-trihydroxy-9-keto prost-13-enoic acid (19-hydroxy PGE1) and 11α,15,19-trihydroxy-9-keto prosta-5,13-dienoic acid (19-hydroxy PGE2) were present at an average total concentration of 100 µg ml−1. These compounds can be isolated together as the methyl ester/methyl oxime derivatives by thin layer chromatography and the individual components can be separated by gas chromatography as the methyl ester/methyl oxime/tert-butyl dimethyl silyl ethers4.

P. L. Taylor

Papers

19-HydroxyIated E prostaglandins as the major prostaglandins of human semen