Colorectal cancer (CRC) remains a leading cause of cancer death, with highest incidence in westernized populations. The pathogenic sequence is well-understood, with characteristic genetic and biochemical abnormalities underlying the adenoma-carcinoma progression . The long phase of progressive premalignant lesions, coupled with the availability of appropriate investigations, provides an opportunity for intervention and primary prevention. A number of chemopreventative strategies have been postulated. There is substantial evidence that diet modifies risk, [2, 3] and oral agents that show promise include folate, statins, calcium, ursodeoxycholic acid and cyclooxygenase (COX) inhibitors [4–7].
Metabolites of arachidonic acid (AA) are important mediators in the adenoma-carcinoma sequence [8–10]. COX and 5-lipoxygenase (5-LOX) are the key enzymes involved in the generation of prostaglandins and leukotrienes respectively from this precursor. These were originally identified as playing important roles in the modulation of inflammation. Cyclooxygenase has two isoforms: COX-1 and COX-2. The former is constitutively expressed in most tissues, whereas the latter is an immediate-to-early response gene . It is undetectable in most normal tissues, but is upregulated in colorectal neoplasms and their precursor lesions,  in which levels of downstream prostaglandin E2 (PGE2) are also elevated . Genetic manipulation studies have shown a causal role for COX-2 in carcinogenesis in cytological and animal models [14–16]. Inhibition of COX-2 activity reverses CRC carcinogenesis in these systems,  and has been shown to induce apoptosis, and inhibit proliferation and angiogenesis [18, 19]. Similar data have also recently emerged for 5-LOX [20, 21]. Expression of 5-LOX has been demonstrated in some cancer cells and is involved in the pathogenesis of cancer. Interestingly, 5-LOX appears to have similar mechanisms to COX-2 in the regulation of cell viability, although these two enzymes often utilize different signaling pathways. Furthermore, it was suggested that arachidonic acid might be shunted from one pathway to the other when a particular pathway is inhibited in the cellular processes of cancer  and inflammation .
COX inhibitors are potentially attractive drugs for the chemoprevention of colorectal cancer, and have been reported to induce regression of polyps in patients with familial adenomatous polyposis . Observational studies suggest a protective effect of non-steroidal anti-inflammatory drugs (NSAIDs),  which non-specifically inhibit COX-2 and its isoform COX-1. Use of these agents is, however, unfortunately limited by gastrointestinal and renal side-effects . Specific COX-2 inhibitors were developed to circumvent these issues, although reports suggest that they are associated with significant cardiovascular adverse effects .
Studies evaluating anti-carcinogenic properties of COX-2 inhibitors however have not shown consistent results. There is a mismatch between the growth-suppressing effect of COX-2 inhibitors [28, 29] and pro-carcinogenic effect of prostaglandins . It is possible that the shunting of AA between COX-2 and 5-LOX that utilize AA will bypass COX-2 inhibition. In cells expressing both enzymes, inhibition of one in isolation may shunt metabolism preferentially down the other pathway, leading to paradoxically increased production of selected eicosanoids. In the presence of COX-2 and 5-LOX expression in cancer cells, combined inhibition of these pathways would likely to be a more effective anti-cancer modality with fewer side-effects.
Here we investigated the effects of NSAIDs on eicosanoid production from colorectal cancer cell lines expressing different level of COX-2 and its consequent anti-neoplastic effects. In this study, we hypothesized that in the presence of shunting between COX-2 and 5-LOX pathway, COX-2 inhibition might fail to show anti-cancer effect irrespective of COX-2 expression. Thus shunting of AA between COX-2 and 5-LOX pathways that utilize AA may bypass COX-2 inhibition.