Mini-reviewCyclooxygenases in cancer: progress and perspective
Introduction
Aspirin was introduced as an anti-pyretic, anti-inflammatory and analgesic drug at the end of nineteenth century. Soon after, a family of drugs with similar properties were discovered and collectively termed non-steroidal anti-inflammatory drugs (NSAIDs). In the late 1960s work from Samuelsson and Bergstrom revealed the prostaglandin synthesis pathways [1], [2], [3] and a few years later, J.R. Vane and his colleagues identified the therapeutic target of NSAIDs as the cyclooxygenase (COX) enzyme [4]. The Noble Prize for Physiology or Medicine was awarded to Drs. Vane, Samuelsson and Bergstrom in 1982 ‘for their discoveries concerning prostaglandins and related biologically active substances’ [5]. Both epidemiological and randomized clinical trials have indicated efficacy, albeit not uniformly, in the ability of aspirin and/or NSAIDs to decrease colorectal cancer [6], [7], [8], [9].
A number of epidemiological studies have indicated that long term aspirin/NSAID use is associated with 30–50% reduction in risk of colorectal cancer or adenomatous polyps or death from colorectal cancer [10]. In addition, these studies suggest that the duration and the consistency of NSAID use are more important than the dosage. Other epidemiologic studies also found associations between NSAID use and a lower death rate from cancers of the esophagus, stomach, breast, lung, prostate, urinary bladder and ovary [11], [12].
Meanwhile, Dr. William Waddell reported the regression of rectal polyps in a small number of familial adenomatous polyposis (FAP) patients in response to the NSAID sulindac [13], [14]. This work has been extended by a number of epidemiological studies as well as clinical trials. The results from the completed randomized double-blind placebo controlled trial on FAP patients suggest that sulindac and celecoxib cause adenoma regression in some polyposis patients, and in some cases, a complete regression is seen [15], [16], [17], [18], [19]. Clinical trials on other high risk populations have generally shown a beneficial reduction in adenoma number and/or size, although the effects are inconsistent [9], [20], [21], [22], [23], [24]. In young FAP patients who were entered into a randomized clinical trial prior to the development of colorectal adenomas, there was no significant effect of sulindac on preventing de novo adenoma formation [25]. In a large scale randomized clinical trial to determine the ability of aspirin to prevent myocardial infarction, there was no reduction in colorectal cancer in the patients receiving aspirin in a secondary analysis [26]. Taken together, despite the early very promising results, currently there is not sufficient evidence to recommend wide-spread use of any of these agents for primary prevention of colon cancer. More clinical trials are ongoing with aspirin, sulindac, celecoxib and refocoxib and we await the results of these trials to provide a more complete estimate of the chemo-preventative value of NSAIDs.
Section snippets
Cyclooxygenase genes and enzymes
In 1988, three different groups cloned a gene encoding cyclooxygenase, which later turned out to be the constitutive isoform—COX-1 [27], [28], [29]. Subsequently, the inducible isoform of COX was discovered and named—COX-2 [30], [31], [32], [33]. The human gene encoding the COX-1 enzyme (PTGS1) is located on chromosome 9 (9q32–9q33.3), contains 11 exons and spreads across 40 kb; its mRNA is approximately 2.8 kb [34]. The gene encoding COX-2 (PTGS2) is located on chromosome 1 (1q25.2–25.3),
Functions of cyclooxygenases
Prostaglandins were first discovered in semen or in the extract of prostate as lipid soluble compounds with potent vasodepressor and smooth muscle-stimulating activity. They were named based on the fact that they were believed to be derived from the prostate [45], [46]. Now it is clear that the normal human prostate itself is not the major source of prostaglandins. The large amounts of prostaglandins in the semen are derived from the nearby seminal vesicles, which are one of the most abundant
Structure of cyclooxygenases
COX-1 and COX-2 share the same substrates, generate the same products, and catalyze the same reaction using identical catalytic mechanisms. When the X-ray crystal structures of these two enzymes were solved, both human and murine COX-2 could be largely superimposed on that of COX-1, with the amino acids serving as the substrate binding pocket and catalytic site being nearly identical to each other. One exception with profound implications is that the isoleucine 590 around the substrate channel
Genetic evidence for an association between COX-2 and cancer
The studies from a murine model of FAP (mice carrying APCΔ716) provided the first genetic evidence for a link between COX-2 and carcinogenesis. When APCΔ716 mice were crossed with mice containing targeted mutations that inactivate the Pgst2 gene (homozygous or heterozygous), the size and number of small intestinal and colonic polyps, especially the number of large polyps were reduced in a dose-dependent manner in comparison with the Pgst2 wide-type littermates [59]. Deletion of the gene (Pla2g4
Role of COX-2 in angiogenesis
The ability to induce angiogenesis is essential for most solid tumors to grow beyond 2–3 mm in diameter. Angiogenesis may also provide an important path for metastasis. Tumor angiogenesis, as with other neovascular formations, includes destabilization of pre-existent blood vessels, proliferation of vascular endothelial cells, invasion by endothelial cells into the extracellular matrix (ECM) and finally the migration and positioning of endothelial cells. One of the earliest observations regarding
Expression in normal tissues
Although COX-2 protein is undetectable by immunohistochemistry in many human tissues under normal physiological conditions, there are several known exceptions. The seminal vesicles are known to have the high levels of constitutive expression of COX-2. PGE2 and its 19-hydroxy metabolites are the major components of primate semen [97]. COX-2 is also constitutively expressed in the kidney with positive staining in glomeruli and small blood vessels. The limited evidence on human subjects suggests
Other unresolved issues and opportunities in NSAID mechanisms of action
The fact that chronic or acute inflammation is commonly associated with cancer also complicates the interpretation of COX-2 expression in cancer. On one hand, the tissue disruption and cell death in cancer recruit pro-inflammatory cells and lead to inflammation. On the other hand, some types of infections or chronic inflammation are causative for the initiation of certain cancers, such as chronic hepatitis, chronic gastritis and chronic ulcerative colitis. Prostaglandins generated as a result
Summary
More than a century after the introduction into the market, aspirin is still a somewhat ‘magical’ drug that can not only prevent inflammation, and reduce pain, but can also prevent cancer. In the past 10 years, our understandings of the molecular biology of COX enzymes, from structure to catalytic mechanisms, have begun to provide evidence from multiple angles to support the pro-carcinogenic role of COX enzymes. One of the most important major issues that remain relates to the expression
Note added in proof
A recent study (Y.G. Crawford, M.L. Gauthier, A. Joubel, K. Mantei, K. Kozakiewicz, C.A. Afshari, T.D. Tlsty, Histologically normal human mammary epithelia with silenced P16INK4a over express COX-2, promoting a premalignant program, Cancer Cell 5 (2004) 263–273.) provides new evidence for a role of COX-2 in breast carcinogenesis.
Acknowledgements
Funded by Public Health Services NIH/NCI #R01CA084997, NIH/#R01CA70196 and NIH/NCI Specialized Program in Research Excellence (SPORE) in Prostate Cancer #P50CA58236.
References (147)
- et al.
Non-steroidal anti-inflammatory drugs and molecular carcinogenesis of colorectal carcinomas
Lancet
(2003) - et al.
Sulindac for polyposis of the colon
Am. J. Surg.
(1989) - et al.
Sulindac causes regression of rectal polyps in familial adenomatous polyposis
Gastroenterology
(1991) - et al.
Colorectal cancer and nonsteroidal anti-inflammatory drugs
Adv. Pharmacol.
(1997) - et al.
Isolation and characterization of the complementary DNA for sheep seminal vesicle prostaglandin endoperoxide synthase (cyclooxygenase)
J. Biol. Chem.
(1988) - et al.
Primary structure of sheep prostaglandin endoperoxide synthase deduced from cDNA sequence
Fed. Eur. Biochem. Soc. Lett.
(1988) - et al.
Molecular cloning of human prostaglandin endoperoxide synthase type II and demonstration of expression in response to cytokines
J. Biol. Chem.
(1993) - et al.
A serum- and glucocorticoid-regulated 4-kilobase mRNA encodes a cyclooxygenase-related protein
J. Biol. Chem.
(1991) - et al.
Assignment of the human prostaglandin-endoperoxide synthase 2 (PTGS2) gene to 1q25 by fluorescence in situ hybridization
Genomics
(1994) - et al.
N-glycosylation of prostaglandin endoperoxide synthases-1 and -2 and their orientations in the endoplasmic reticulum
J. Biol. Chem.
(1993)
Epidermal growth factor-induced actin remodeling is regulated by 5- lipoxygenase and cyclooxygenase products
Cell
MAP kinase pathways as a route for regulatory mechanisms of IL-10 and IL-4 which inhibit COX-2 expression in human monocytes
Biochem. Biophys. Res. Commun.
Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2
J. Biol. Chem.
Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin
J. Biol. Chem.
Mutation of serine-516 in human prostaglandin G/H synthase-2 to methionine or aspirin acetylation of this residue stimulates 15-R-HETE synthesis
Fed. Eur. Biochem. Soc. Lett.
Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs
J. Biol. Chem.
Prostaglandin H synthase-1: evaluation of C-terminus function
Arch. Biochem. Biophys.
Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2)
Cell
Suppression of intestinal polyposis in Apc(delta 716) knockout mice by an additional mutation in the cytosolic phospholipase A(2) gene
J. Biol. Chem.
Roles of prostanoids revealed from studies using mice lacking specific prostanoid receptors
Jpn. J. Pharmacol.
Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice
J. Biol. Chem.
Indomethacin enhancement of TPA tumor promotion in mice
Cancer Lett.
Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration
Cell
Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse
Cell
Multiple female reproductive failures in cyclooxygenase 2-deficient mice
Cell
Cyclooxygenase regulates angiogenesis induced by colon cancer cells (published erratum appears in Cell 94 (2) (1998 Jul 24) following 271)
Cell
Activation of matrix metalloproteinase-2 in human breast cancer cells overexpressing cyclooxygenase-1 or -2
Fed. Eur. Biochem. Soc. Lett.
Alterations in cellular adhesion and apoptosis in epithelial cells overexpressing prostaglandin endoperoxide synthase 2
Cell
Tumorigenic transformation of immortalized ECV endothelial cells by cyclooxygenase-1 overexpression
J. Biol. Chem.
The 3′-untranslated region of murine cyclooxygenase-2 contains multiple regulatory elements that alter message stability and translational efficiency
J. Biol. Chem.
Prostaglandins: enzymatic analysis
Science
The prostaglandins
Endeavour
Absolute configuration of the prostaglandins
Nature
Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs
Nat. New Biol.
Colorectal cancer prevention by non-steroidal anti-inflammatory drugs: effects of dosage and timing
Br. J. Cancer
COX-2: a target for colon cancer prevention
Annu. Rev. Pharmacol. Toxicol.
The potential of non-steroidal anti-inflammatory drugs (NSAIDs) for colorectal cancer prevention
J. Surg. Oncol.
Reduced incidence of colorectal adenoma among long-term users of nonsteroidal antiinflammatory drugs: a pooled analysis of published studies and a new population-based study
Epidemiology
Epidemiological and clinical aspects of nonsteroidal anti-inflammatory drugs and cancer risks
J. Environ. Pathol. Toxicol. Oncol.
Nonsteroidal anti-inflammatory drugs as anticancer agents: mechanistic, pharmacologic, and clinical issues
J. Natl Cancer Inst.
Sulindac for polyposis of the colon
J. Surg. Oncol.
Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis
N. Engl. J. Med.
Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis
Br. J. Surg.
The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis
N. Engl. J. Med.
Effects of piroxicam on prostaglandin E2 levels in rectal mucosa of adenomatous polyp patients: a randomized phase IIb trial
Cancer Epidemiol. Biomarkers Prev.
A randomized trial of aspirin to prevent colorectal adenomas
N. Engl. J. Med.
A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer
N. Engl. J. Med.
Effect of subacute ibuprofen dosing on rectal mucosal prostaglandin E2 levels in healthy subjects with a history of resected polyps
Cancer Epidemiol. Biomarkers Prev.
Suppression of human colorectal mucosal prostaglandins: determining the lowest effective aspirin dose
J. Natl Cancer Inst.
Cited by (367)
Recent trends and advances in the epidemiology, synergism, and delivery system of lycopene as an anti-cancer agent
2021, Seminars in Cancer BiologySymmetrical and un-symmetrical curcumin analogues as selective COX-1 and COX-2 inhibitor
2021, European Journal of Pharmaceutical SciencesCurcumin induces expression of 15-hydroxyprostaglandin dehydrogenase in gastric mucosal cells and mouse stomach in vivo: AP-1 as a potential target
2020, Journal of Nutritional BiochemistrySynthesis, structure and anti-cancer activity of osmium complexes bearing π-bound arene substituents and phosphane Co-Ligands: A review
2020, European Journal of Medicinal ChemistryCancer: Thymoquinone antioxidant/pro-oxidant effect as potential anticancer remedy
2019, Biomedicine and PharmacotherapyCitation Excerpt :Peroxynitrite induces DNA single-strand breakage beside being a stressful condition that causes excessive lipid peroxidation and oxidative stress [97]. Prostaglandins are splitted from plasma membrane arachidonic acid in response to NF-κB and cytokines activated COX-2 [98]. Prostaglandins play a substantial role in tumerogenesis via immunomodulation, angiogenesis and DNA damage by lipid peroxidation [91].