Evidence indicates that colorectal tumors are infiltrated by various types of immune cells, including neutrophils, mast cells, natural killer cells, dendritic cells, and tumor-associated macrophages. They exhibit overexpression of inflammatory genes, including cyclooxygenase COX -2, nuclear factor B, Stat3, inducible nitric oxide synthase, and inflammatory cell infiltration is a hallmark of colorectal tumor progression [ 12 , 13 ].
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Epidemiological and clinical trial studies support the importance of nonsteroidal anti-inflammatory drugs NSAIDs in the reduction of the risk of colon cancer [ 11 , 12 ]. Unequivocal evidence for the inhibitory effects of several NSAIDs on CRC was provided by our laboratory and others using animal models of colon cancer [ 12 - 16 ]. Among all of the NSAIDs, aspirin has been most extensively studied at clinical both observational and randomized and preclinical levels and has been found to have colon cancer chemopreventive properties [ 13 , 17 - 20 ].
A recently published study [ 21 ] supports the usefulness of aspirin for prevention of CRC and other cancers. This finding is especially significant because of the association of serrated polyps in the proximal colon with the greater difficulty in diagnosing these proximal polyps by colonoscopy screening. Preclinical studies from our laboratory and others have shown that administration of aspirin significantly inhibits the formation of chemically induced colonic tumors in rodent models [ 20 , 22 ]. The role of COX-2 in colon tumorigenesis has been well established and served as the rationale for development of selective COX-2 inhibitors.
Studies from our laboratory and others have shown that the selective COX-2 inhibitor celecoxib suppresses colon cancer development much more efficiently than the nonselective COX inhibitors and that it has fewer side effects [ 23 , 24 ]. COXselective inhibitors definitely hold advantages over COX-1 inhibitors because of their limited gastrointestinal toxicity [ 25 ].
Clinical trials with celecoxib and rofecoxib have shown that these agents provide significant chemopreventive efficacy against sporadic polyp development; however, the requirement of high doses and the increased occurrence of cardiovascular events have been deterrents for widespread clinical application [ 26 - 28 ].
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Long-term clinical observations suggest that COXselective inhibitors may contribute to increased cardiovascular risk in individuals with prothrombotic conditions [ 29 , 30 ]. In addition, inhibition of COX activity leads to a shift from the AA pathway to the 5-lipoxygenase 5-LOX pathway and formation of protumorigenic and prothrombotic metabolites [ 31 ] illustrated in Fig. It is important to develop new strategies that target 5-LOX and COX-2 to gain maximal efficacy without unwanted side effects, particularly prothrombotic effects that pose a risk of fatal cardiovascular events.
Arachidonic acid is produced from membrane phospholipids as part of a major pathway involved in pain and inflammation. Arachidonic acid is further metabolized by lipoxygenase and cyclooxygenase pathways. Among lipoxygenases, 5-LOXs produce leukotrienes, which play major roles in inflammation and gastrointestinal GI damage and contribute to protumorigenic conditions. One of the leukotrienes is converted to lipoxin A 4 through lipoxygenase and helps in resolving inflammatory conditions; it exhibits antitumorigenic activity.
The cyclooxygenase pathway produces prostaglandin H 2 PGH 2 , which serves as a substrate for conversion to various other prostaglandins. Many prostaglandins and thromboxanes have proinflammatory and prothrombotic effects, leading to increased risk of potentially fatal cardiovascular events. In recent years, a critical role of 5-LOX in the regulation of cell proliferation and apoptosis has emerged [ 32 - 34 ].
A number of reports document that 5-LOX is overexpressed in cancer cells and human tumors, including those of the colon, lung, breast, prostate, pancreas, bone, brain, and mesothelium [ 36 - 39 ]. In vitro and nude mouse studies indicate that 5-LOX overexpression is associated with increased proliferation and tumor growth [ 40 ]. Studies by Ohd et al. Thus, upregulated 5-LOX expression appears to be associated with neoplastic transformation, although the sequence of events connecting 5-LOX gene expression to colon cancer development is unknown.
A role for COX-2 in colon tumorigenesis has been well established through use of COX-2 knockout mice models [ 41 , 42 ]. However, comparable information with 5-LOX knockout mice in colon carcinogenesis is lacking. They used an antisense method to block 5-LOX expression and confirmed a role of 5-LOX in promoting cancer cell proliferation. Several studies suggest that activation of 5-LOX, with accumulation of 5- S -HETE and leukotrienes, is triggered by colon-tumor-promoting bile acids and carcinogens [ 47 ]. Previously, we have shown that treatment of rats with the colon carcinogen azoxymethane AOM leads to increased activity of 5-LOX in the colon [ 48 , 49 ].
The exact mechanism by which 5-LOX or its metabolites regulate cell proliferation and apoptosis is not fully established. LTB 4 has been shown to inhibit apoptosis [ 46 ]. A possible mechanism by which 5-LOX metabolites could regulate colon tumor cell growth is through their electrophilic activity and generation of reactive lipid metabolites, which can impair translocation of the transcription factor p53 to nuclei.
We and others have shown previously that electrophilic prostaglandins dose-dependently induce the accumulation of p53 in cytosol rather than in nuclei of colon cancer cell lines, and that COXselective inhibitors can reverse the cytosolic p53 accumulation [ 53 ]. The prevention of p53 nuclear accumulation by electrophiles might represent a mechanism by which 5- S -HETE, leukotrienes, and prostaglandins suppress pmediated apoptosis in colon carcinogenesis.
The physiological role of 5-LOX in cells of the myeloid lineage has been studied extensively [ 52 , 53 ]; however, abnormal overexpression, which leads to inflammation and prothrombotic and protumorigenic effects, has come under investigation only recently [ 54 - 56 ]. Leukotrienes play a major role in the inflammatory process and are implicated in a number of inflammatory diseases [ 59 , 60 ,]. LTB 4 is a potent stimulator of leukocyte activation, and adhesion of these cells to vascular endothelium elicits chemokinetic and chemotactic responses [ 61 - 64 ].
Mehrabian and colleagues have demonstrated that inflammatory eicosanoids derived from increased 5-LOX expression—LTB 4 and the cysteinyl leukotrienes—are active in the vasculature during thrombosis. They have been shown to promote inflammatory cell activation, cell proliferation, and vasoconstriction [ 65 , 66 ].
However, in the setting of inflammatory conditions, e. The shifting of the flux of arachidonate through the 5-LOX pathway by inhibiting COX activity is of major importance in the increased cardiovascular risks associated with COXselective inhibitors. The exact molecular mechanisms by which COX-2 inhibition leads to increased prothrombotic effects is yet to be fully understood; but, several studies support a role for 5-LOX-derived metabolites in prothrombotic effects [ 69 , 70 ]. Clinical observations suggest that prolonged administration of COX-2 inhibitors is required to modify thrombotic risk, and a reasonable culprit for the aberrant thrombotic response is the platelet [ 71 , 72 ].
With COX-2 inhibition, there is an increase in the number of coated platelets, which have exposed phosphatidylserine and retention of several procoagulant proteins on the their surfaces; and these coated platelets support a robust prothrombinase activity [ 73 - 75 ]. The consequences of too many coated platelets remain speculative in preclinical models, but the prothrombotic characteristics of coated platelets suggest that they have the potential to induce thrombotic responses. Some studies suggest that chronic stimulation of the immune system or inflammation might be a cause of elevated numbers of coated platelets [ 76 ].
Given the anti-inflammatory nature of COX-2 inhibitors, a potential role for them in increasing production of coated platelets seems counterintuitive. However, the facts that 5-LOX and COX-1 remain active during COX-2 inhibition and that the mediators responsible for modulating production of coated platelets are present at high concentrations make this a feasible hypothesis.
One clinical observation supports the implication of COX-2 inhibitors in modulating coated platelet production. In a case report, Rashid et al. Targeting COX-2 for colon cancer has been well established in preclinical and clinical studies as discussed already. Similarly, administration of zileuton and celecoxib in combination provided additive chemopreventive effects when compared with a single agent alone against dimethylbenzanthracene-induced oral cancers in hamsters [ 81 ].
Zileuton Leutrol , a selective 5-LOX inhibitor of the N -hydroxyurea series developed by Abbott Laboratories, is the first orally active leukotriene inhibitor to show clinical efficacy in humans [ 82 ]. Zileuton is commonly used for the treatment of bronchial asthma. Several highly selective 5-LOX inhibitors are available; however, their anticarcinogenic properties are not fully established in preclinical studies. Zileuton was evaluated for its efficacy in heterotopic xenograft models using HT29 and LoVo human colon cancer cells.
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The 5-LOX inhibitor Rev and nordihydroguaiaretic acid—a nonspecific lipoxygenase LOX inhibitor—were studied for their effects on DNA synthesis via thymidine incorporation and cell counting. Inhibition of 5-LOX was shown to decrease DNA synthesis in a concentration- and time-dependent manner in the human colon cancer cells and to decrease tumor growth in the xenograft models.
Rev also showed strong cytotoxic effects in various cancer cell lines and chemopreventive activity against colorectal adenocarcinoma xenografts. These studies support the conclusion that 5-LOX is an important target; they show that blockade of 5-LOX inhibits colon cancer cell proliferation both in vitro and in vivo and they suggest that 5-LOX inhibitors may provide a beneficial chemopreventive therapy in colon cancer [ 83 ]. Other 5-LOX inhibitors, such as AA, have been shown to have similar effects in human colon cancer cells [ 85 ]. Curcumin, a major pigment in turmeric, has been identified as having anti-inflammatory and antioxidant properties [ 87 ].
It has been well studied for its anti-inflammatory roles in acute and chronic rat and mouse models. Its anti-inflammatory activity has been confirmed in clinical studies in patients with postoperative inflammation. It has been shown to reduce symptoms associated with rheumatoid arthritis, confirming its role in signaling pathways related to inflammation [ 87 ]. Dietary administration of curcumin 0. We reported that 0. In vitro results in macrophage Raw Phenylethyl caffeate PEC and phenylethylmethyl caffeate PEMC are the phenolic constituents of honey that significantly inhibit proliferation of HT 29 human colon cancer cells [ 90 ].
Administration of PEMC at ppm in the diet significantly inhibited the incidence and multiplicity of AOM-induced invasive adenocarcinomas These results suggest that caffeic acid esters exhibit anti-inflammatory effects by suppressing LOX signaling pathways.
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The ethanolic extracts of Terminalia chebula fruits used to treat many diseases, such as diabetes, digestive diseases, colic pain, chronic cough, sore throat, and asthma were tested for their ability to inhibit COX and 5-LOX. One of the fractionated compounds, chebulagic acid, showed potent dual inhibition against COX and 5-LOX and antiproliferative activity. Recent studies demonstrating the gastrointestinal and cardiovascular toxicities of NSAIDs have prompted the search for novel approaches and agents with similar or higher efficacies.
The combination treatment of celecoxib and AA at their lower doses showed a more pronounced inhibitory action than treatment with either inhibitor alone [ 80 ]. Celecoxib and the 5-LOX inhibitor MK were studied for their effects on PGE 2 and cysteinyl leukotriene production and on tumor cell proliferation in the Caco-2 and HT29 human colon cancer cell lines. However, the combination treatment of celecoxib plus MK could prevent this activation and had additive effects on inhibition of tumor cell proliferation in comparison with treatment with either inhibitor alone.
Licofelone exhibits anti-inflammatory, analgesic, and antipyretic properties at a dose that causes no gastrointestinal damage [ 95 , 96 ]. Preclinical and clinical phase I and II studies on licofelone suggest that this agent possesses several advantages when compared with general NSAIDs indomethacin, aspirin, naproxen and COXspecific inhibitors celecoxib, rofecoxib in efficacy; and, more importantly, licofelone has no gastrointestinal side effects [ 96 ]. Administration of licofelone to male F rats significantly inhibited the formation of AOM-induced aberrant colonic crypt foci preneoplastic lesions in a dose-dependent manner and caused a significant dose-dependent decrease in the COX-2 and 5-LOX activities [ 98 ].
Lipoxygenase and Cyclooxygenase Pathways and Colorectal Cancer Prevention
On the basis of these published studies and our additional preliminary data, we suggest that licofelone will be an ideal agent to develop as a novel colon cancer chemopreventive agent. Omega-3 fatty acids cannot be synthesized in the body and are obtained from diet. Foods rich in omega-3 fatty acids include walnuts, flaxseeds, rapeseeds, and fish. In the absence of PUFAs, AA is metabolized to the 2-series of prostaglandins and thromboxanes, most of which are proinflammatory, and the 4-series of leukotrienes.
Prostaglandin H 2 is the immediate precursor of all 2-series prostaglandins and thromboxanes. These AA-derived eicosanoids play a vital role in eliciting immune responses, in inducing inflammation, and in resolution of inflammation. The presence of omega-3 fatty acids inhibits the formation of the 2-series prostaglandins and increases production of 3-series prostaglandins and 5-series leukotrienes. PUFAs also lead to generation of resolvins and lipoxins, which are anti-inflammatory in function [ 99 ]. Hence, omega-3 fatty acids reduce COX-2 and 5-LOX activities and the production of proinflammatory eicosanoids, supporting their use as anti-inflammatory and antitumorigenic agents in colon cancer.
Low-dose aspirin leads to acetylation of COX-2 and to generation of R -hydroxyeicosapentaenoic acid. This intermediate is further reduced to the hydroxyl compound by 5-LOX, and then undergoes a further reduction step to generate resolvin 2, and eventually, resolvin 1, which provides anti-inflammatory function. Resolvins have been shown to attenuate colonic mucosal inflammation in animals [ ].
One of the methods of lipoxin generation is through low-dose aspirin generating epi -lipoxin A4 or epi -lipoxin B4 via 5-LOX. These products are called aspirin-triggered lipoxins; they possess potent anti-inflammatory functions similar to endogenous lipoxins. Lipoxins antagonize the functions of leukotrienes and have anti-inflammatory functions in colitis and an antiproliferative function in human colon cancer cell lines [ 99 ]. More detailed in-depth studies are necessary to understand the role of lipoxins in colon cancer prevention. CRC is major health problem worldwide, with over 1.
Extensive studies of the pathobiological processes in CRC suggest that inflammation is a major hallmark of colon tumor progression leading to adenocarcinoma. Among the various inflammatory mediators, arachidonate-derived eicosanoids, particularly COX-2 and 5-LOX metabolites, are well established as major contributors to colorectal tumor development.
COX-2 Blockade in Cancer Prevention and Therapy
General NSAIDs and COXselective inhibitors have proven to be highly efficient in the prevention of CRC at both preclinical and clinical levels; however, their frequent use in high doses and for long periods is associated with gastrointestinal ulcerations and increased risk of prothrombotic events in individuals at high risk of colon cancer. Recent advances in understanding the 5-LOX pathway and its contribution to the risk of CRC thrombosis support the targeting of this pathway along with COX-2 in cancer prevention and therapy.
This finding need to be validated further in human clinical trials. Overall, the roles of 5-LOX and COX-2 in colon tumor development are becoming well established, and targeting both of these pathways is an important strategy for CRC prevention and treatment. Disclosure No potential conflicts of interest relevant to this article were reported.
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Curr Colorectal Cancer Rep. Author manuscript; available in PMC Dec 1. Rao , Naveena B. Janakiram , and Altaf Mohammed. Author information Copyright and License information Disclaimer. See other articles in PMC that cite the published article. Abstract Colorectal cancer is one of the commonest malignancies in both men and women.
Inflammation and Nonsteroidal Anti-inflammatory Drugs Over the past few decades, preclinical, clinical, and extensive mechanistic studies have supported the importance of inflammatory mediators, particularly inflammatory cytokines and arachidonic acid AA -derived eicosanoids, in the pathogenesis of CRC. Open in a separate window. Conclusions CRC is major health problem worldwide, with over 1.
Acknowledgment The authors are supported by a grant from the National Cancer Institute. Footnotes Disclosure No potential conflicts of interest relevant to this article were reported. Skip to content Skip to search. Humana Press ; [Oxford: Language English View all editions Prev Next edition 3 of 3. Series Cancer drug discovery and development Subjects Cancer -- Chemoprevention. Cyclooxygenase 2 -- Inhibitors -- Therapeutic use.
Contents Machine derived contents note: Reddy and Chinthalapally V. Alshafie, and Randall E. Gupta and Raymond N.
Harmon, and Jaime L. Richards and Robert W. Hsi and Thomas E. Steele, and Caroline C. Anderson, Asad Umar, Jaye L. Viner, and Ernest T. Widening the Scope of Impact 3 Index 3.