A wide array of phenolic substances, particularly those present in edible and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Cyclooxygenase-2 (COX-2) inducible and nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. Improper up-regulation of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage. Examples are curcumin, a yellow pigment of turmeric (Curcuma longa L., Zingiberaceae), the green tea polyphenol epigallocatechin gallate (EGCG), and resveratrol from grapes (Vitis vinifera, Vitaceae) that strongly suppress tumor promotion. Recent studies have demonstrated that eukaryotic transcription factor nuclear factor-kappa B (NF-kappa B) is involved in regulation of COX-2 and iNOS expression. Several chemopreventive phytochemicals have been shown to inhibit COX-2 and iNOS expression by blocking improper NF-kappa B activation. Multiple lines of compelling evidence indicate that extracellular-regulated protein kinase and p38 mitogen-activated protein kinase are key elements of the intracellular signaling cascades responsible for NF-kappa B activation in response to a wide array of external stimuli. Curcumin, EGCG and resveratrol have been shown to suppress activation of NF-kappa B. One of the plausible mechanisms underlying inhibition of NF-kappa B activation by aforementioned phytochemicals involves repression of degradation of the inhibitory unit I kappa B alpha, which hampers subsequent nuclear translocation of the functionally active subunit of NF-kappa B.

Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation.

Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4.

Aspirin and other nonsteroidal antiinflammatory drugs inhibit prostaglandin synthesis and tumor growth in many experimental systems, but it is unclear which of these tumor models are relevant to humans. We have reported reduced risk of fatal colon cancer among persons who used aspirin in a large prospective study. This analysis examines other fatal cancers in relation to aspirin among 635,031 adults in that study who provided information in 1982 on the frequency and duration of their aspirin use and did not report cancer. Death rates were measured through 1988. Death rates decreased with more frequent aspirin use for cancers of the esophagus, stomach, colon, and rectum but not generally for other cancers. For each digestive tract cancer, death rates were approximately 40% lower among persons who used aspirin 16 times/month or more for at least 1 year compared to those who used no aspirin. The trend of decreasing risk with more frequent aspirin use was strongest among persons who had used aspirin for 10 years or more; it remained statistically significant, except for esophageal cancer, in multivariate analyses that adjusted for other known risk factors. Biases such as early detection or aspirin avoidance among cases do not appear to explain the results. Our data suggest that regular, prolonged use of aspirin may reduce the risk of fatal cancer of the esophagus, stomach, colon, and rectum. Future epidemiological and basic research should examine all digestive tract cancers in considering the chemopreventive or therapeutic potential of nonsteroidal antiinflammatory drugs.

https://cancerres.aacrjournals.org/content/canres/53/6/1322.full.pdf

Aspirin Use and Risk of Fatal Cancer

This review is aimed at providing readers with a comprehensive reference article about the distribution and function of P2 receptors in all the organs, tissues, and cells in the body. Each section provides an account of the early history of purinergic signaling in the organ/cell up to 1994, then summarizes subsequent evidence for the presence of P2X and P2Y receptor subtype mRNA and proteins as well as functional data, all fully referenced. A section is included describing the plasticity of expression of P2 receptors during development and aging as well as in various pathophysiological conditions. Finally, there is some discussion of possible future developments in the purinergic signaling field.

/pdf/cellular-distribution-and-functions-of-p2-receptor-subtypes-32555c8g2p.pdf

Cellular distribution and functions of P2 receptor subtypes in different systems.

The arachidonic acid cascade generates a family of bioactive lipids that modulate diverse physiological and pathophysiological responses. Although there has been a great deal of interest in the involvement of arachidonic acid metabolites in cancer, there is uncertainty about which metabolites are the most im portant and how they contribute to specific steps in cell trans formation, tumor growth, and metastasis (1-9). The complex ity of arachidonic acid metabolism is daunting to neophytes and the multiplicity of responses exerted by a single metabolite can be confusing to the cognoscenti. This has made it difficult to extrapolate results from animal experiments to human beings. A recent report from Thun et al. (10) and previous reports from Rune et al. (11) and Rosenberg et al. (12) suggest that aspirin intake may reduce colon cancer incidence (11, 12) and mortality (10) in the general population. Other studies from Paganini-Hill et al. (13, 14) do not support such an association. Aspirin is a relatively specific inhibitor of one branch of the arachidonic acid cascade and even though there is not universal agreement among these epidemiological investigations, their findings refocus attention on the role of arachidonic acid me tabolites in cancer. This Perspective was written to highlight some of the existing literature on the aspirin-inhibitable branch of the arachidonic acid cascade and cancer, to apply that liter ature to colon cancer where possible, and to identify deficien cies in our knowledge that need to be addressed. Although the major focus is the colon, the mechanistic concepts should be applicable to other organ sites. The Perspective begins with an overview of arachidonic acid metabolism, proceeds to a consideration of the biochemistry and molecular biology of the enzyme inhibited by aspirin, touches on the signal transduction pathways linked to arachi donic acid metabolism, and then considers mechanisms by which specific arachidonic acid metabolites participate in the carcinogenic process. The review is not meant to be compre hensive and apologies are made in advance to colleagues whose work is not highlighted or was inadvertantly omitted.

/pdf/aspirin-and-the-potential-role-of-prostaglandins-in-colon-149n52w61k.pdf

Aspirin and the Potential Role of Prostaglandins in Colon Cancer

EXISTING methods for extracting prostaglandins from tissues or seminal plasma with 70–90% ethanol1 or acetone2 give poor and inconsistent recoveries from blood. Equilibrium dialysis and recovery experiments with labelled and unlabelled prostaglandins show that this is due to binding with precipitated serum albumen (unpublished results of W. G. U.). Plasma globulins and intact blood cells do not seem to interact with the prostaglandins. When precipitation of protein is avoided by using 40–50% ethanol acidified with formic acid, the prostaglandins can be extracted quantitatively into chloroform. The method is as follows: (1) centrifuge heparinized or citrated blood; (2) mix 1 volume each of plasma and saline with 2 volumes of ethanol (analytical grade); (3) extract twice with petrol (boiling point 40°–60° C, 2×2 volumes) to remove neutral fats including carotene; (4) adjust to pH 3–3.5 with formic acid (1–3% v/v); (5) extract twice with amounts of chloroform each equal to the total volume in stage 4; (6) evaporate chloroform in a thin film evaporator at 30° C; (7) re-dissolve residue in 10 ml. chloroform and evaporate to aid the removal of formic acid; (8) blow oxygen-free nitrogen through vessel until odour of formic acid is gone; (9) dissolve in Krebs solution for bioassay or in appropriate solvent for chromatography.

Extraction of Prostaglandins from Human Blood

1. Gas chromatography-mass spectrometry demonstrated the presence of arachidonic acid (AA), 6-keto-prostaglandin F1 alpha and thromboxane B2 (TxB2) in all extracts of homogenized muscle or mucosa from human stomach, terminal ileum or sigmoid colon. Prostaglandin D2 (PGD2), PGE2 or PGF2 alpha were usually found more often in the mucosal extracts. The 12-hydroxy-derivative of AA (12-HETE) was detected in all extracts of the colon but in only some of the other tissues. 2. Most prostanoids tested contracted the longitudinal muscle, the order of potency being U-46619 (an epoxymethano analogue of PGH2) greater than PGE2 greater than PGF2 alpha greater than PGD2; PGI2 usually caused relaxation, whereas its breakdown products or TxB2 had weak and variable effects. 3. U-46619 or, less potently, PGF2 alpha contracted the circular muscle, whereas PGI2 and usually PGE2 caused relaxation. PGD2, 6-keto-PGF1 alpha, 6,15-diketo-PGF1 alpha or TxB2 usually had little or no effect. 4. PGI2 antagonized contractions to some excitatory prostanoids, without greatly affecting contractions to acetylcholine. 5. For both muscle layers there was a gradient in sensitivity to prostanoids along the gastrointestinal tract. The sensitivities were stomach greater than distal ileum greater than sigmoid colon. 6. The results are discussed in relation to gastrointestinal physiology and pathophysiology.

/pdf/metabolites-of-arachidonic-acid-formed-by-human-3dolgfhwld.pdf

Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers.

Cancer growth, response to treatment and survival time in mice: beneficial effect of the prostaglandin synthesis inhibitor flurbiprofen.

1 Prostaglandin-like material was extracted from muscle and mucosa of surgically removed human stomach, ileum and colon and assayed against prostaglandin E(2) on strips of rat gastric fundus. Superfused human isolated gastric mucosa released prostaglandin-like material and release was increased by stretching or clamping the tissue.2 The relative amounts of extracted biological activity were broadly as follows: gastric antral mucosa > colon muscle > gastric body mucosa approximately ileal mucosa > colon mucosa approximately gastric muscle approximately ileal muscle.3 Prostaglandin E and F were tentatively identified by chromatography and sensitivity to inactivation by alkali.4 Prostaglandin E apparently contributed most to the biological activity, possibly because the assay tissue is more sensitive to prostaglandin E than to F. Chromatography of gastric body mucosal extracts located material running with prostaglandin E(2) and a little with E(1). Colonic muscle and mucosal extracts contained material with R(F) values of prostaglandins E(1), E(2), E(3) and F(1a), whereas F(2a) and F(3a)-like substances were found only in the mucosa. The proportions of prostaglandin F varied between specimens.5 The amount of extracted prostaglandin-like activity was increased by adding cofactors and arachidonic acid, and lessened by homogenization with acid-ethanol.6 The type and amount of activity generated from arachidonic acid by partly purified colonic mucosal prostaglandin synthetase depended on the substrate concentration.7 The possible relationships of prostaglandins to mucus secretion and other physiological and pathological gut functions are discussed.

/pdf/estimation-and-characterization-of-prostaglandins-in-the-4fvym6t0ui.pdf

Estimation and characterization of prostaglandins in the human gastrointestinal tract

Lung primary carcinomas and normal tissue from 136 patients have been extracted for prostaglandins, and the findings examined in relation to histology. In most cases, tumours yielded more prostaglandin-like material (PG-lm), as judged by bioassay, than did normal tissue from the same lungs. Amounts varied with tumour types, in the following ascending order: small-cell carcinomas, large-cell undifferentiated carcinomas, well-differentiated squamous carcinomas, poorly-differentiated adenocarcinomas, poorly differentiated squamous carcinomas, and well-differentiated adenocarcinomas. Tumour PG-lm was highest when necrosis or the neutrophil content of the tumours were moderate, whereas PG-lm from normal lung tissue correlated with the number of macrophages. Chromatography indicated the presence of various prostaglandins, in agreement with our recent findings using gas chromatography--mass spectrometry.

I F Stamford

Papers

Extraction of Prostaglandins from Human Blood

Metabolites of arachidonic acid formed by human gastrointestinal tissues and their actions on the muscle layers.

Cancer growth, response to treatment and survival time in mice: beneficial effect of the prostaglandin synthesis inhibitor flurbiprofen.

Estimation and characterization of prostaglandins in the human gastrointestinal tract

Prostaglandins and human lung carcinomas