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Pharmacology and cellular/molecular mechanisms of action of aspirin and Non-aspirin NSAIDs in colorectal cancer

https://doi.org/10.1016/j.bpg.2011.10.016Get rights and content

Colorectal cancer (CRC) and colorectal adenomas have in common a dysfunctional adenomatous polyposis coli suppressor gene (APC). This allows for activation of the oncogenic Wnt/β-catenin pathway, resulting in cytosolic accumulation of β-catenin, its translocation to the nucleus and action as a cofactor for stimulation of gene transcription. Pharmacological approaches of CRC-chemoprevention are focused to prevention of this β-catenin-mediated oncogenic signalling.

Among upregulated genes in tumour tissue is COX-2 which synthesises large amounts of PGE2. PGE2 inhibits apoptosis, acts proinflammatory and immunosuppressive and stimulates tumour angiogenesis and proliferation. In addition, COX-2 causes oxidation (activation) of cocarcinogens. Aspirin and non-aspirin NSAIDs inhibit COX-2, subsequent PGE2 formation and action by transcriptional and non-transcriptional mechanisms. These also include inhibition of generation of sphingosine-1-phosphate, an amplifier of these reactions and stimulation of NSAID-induced gene (NAG-1) which acts as an inhibitor. Aspirin additionally acetylates COX-2, resulting in generation of ‘aspirin-triggered’ lipoxins (ATL), a new class of anti-inflammatory/antitumour compounds. COX-1 inhibition might also contribute to antitumour effects of aspirin, for example at low-dose aspirin.

Experimental evidence suggests additional COX independent actions of aspirin and non-aspirin NSAIDs on oncogenic signalling. This includes modifications of transcription factors (NFκB), induction of apoptosis and DNA stabilization. In comparison to non-aspirin NSAIDs (sulindac, indomethacin) and coxibs (celecoxib), aspirin has the advantage of concomitant antiplatelet effects while NSAIDs rather have a thrombogenic potential. Though these actions of aspirin have to be balanced against an increased bleeding tendency, aspirin is currently the most attractive candidate for clinical CRC chemoprevention. Open questions, such as dose, (minimum) duration of treatment and the individual risk/benefit ratio are subjects of prospective randomized trials which are underway.

Introduction

Malignancies result from gene defects, hereditary or spontaneous in nature, which cannot be corrected in due time by appropriate repair mechanisms [1]. Functional consequences are resistance to apoptosis, imbalanced cell proliferation, angiogenesis and tumour invasion. Colorectal carcinomas (CRC), a heterogeneous group of solid tumours in the intestine, also result from gene defects. These presumably start in intestinal stem cells within the colonic crypt, being able to self-renewal and possible aberrant differentiation in the presence of mutations of regulatory genes [2]. Prevention of these gene defects and/or their consequences for protein expression and function is the optimum treatment strategy, but difficult to realize. In addition to dietary changes with a still unclear benefit, chemoprevention by drugs is an attractive option to manage CRC, also, because the disease has identifiable and treatable precursor lesions – the adenomatous intestinal polype with a long transition time until overt carcinoma develops.

A first evidence for effective chemoprevention of CRC came from the Melbourne Colorectal Cancer study, published more than 20 years ago. In this study, Gabriel Kune and colleagues showed that regular long-term intake of aspirin reduced the risk of colorectal carcinoma (CRC) by 40% [3]. This finding was confirmed in a number of subsequent epidemiological and randomized trials [4], [5]. In addition to aspirin, other COX-inhibitors such as traditional non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. sulindac), also were reported to have a chemopreventive effect on adenoma formation and cancer prevention in observational trials [5], [6]. However, there are not many randomized trials on tumour prevention and a recent phase II preclinical trial, though with small numbers of patients, could not provide convincing evidence of CRC risk reduction from short-term (6-month) intervention [7]. Beneficial results were also found for a COX-2-selective inhibitor (celecoxib) in familial adenomatous polyposis [8], suggesting that COX-2, the inducible form of fatty acid cyclooxygenase (COX) is an important factor in the pathophysiology of CRC. Indeed, upregulation of COX-2, a proliferation-associated ‘immediate-early’ gene, is regularly found in colorectal adenomas and carcinomas and associated with markedly increased PGE2 production while no upregulation has been seen with COX-1 [9], [10], [11], [12]. These data suggest that COX-2 and COX-2-derived products, respectively, are intimately involved in the pathogenesis of CRC and that inhibition of COX-mediated prostaglandin formation might offer a useful treatment option for chemoprevention of CRC [13].

On the other hand, the aetiology and pathophysiology of CRC is complex [1]. Thus, it is rather unlikely that antitumour effects of aspirin and non-aspirin NSAIDs can solely be explained by one mechanism, i.e. inhibition of COX-2-dependent prostaglandin formation [10], [13], [14], [15], [16]. Aspirin and nonaspirin NSAIDs have numerous actions on gene transcription and protein synthesis in inflammation and tumorigenesis in addition to inhibition of prostaglandin biosynthesis [17]. This is particularly true for the high concentrations used in cell culture assays (see below). Interestingly, these compounds were found to promote apoptosis and to inhibit cell proliferation in human CRC cell lines which did not express COX-2 and this effect was not reversed by prostaglandin treatment [18], [19].

Chemopreventive actions of aspirin and non-aspirin NSAIDs have also been reported with other solid tumours. However, the most convincing data were obtained in prevention of malignancies of the gastrointestinal tract [14]. In addition to CRC, this includes malignant tumours from the oesophagus and stomach [20]. Elevated COX-2 expression in relation to tumorigenesis was shown in all of them [21], [22] and preliminary evidence suggests that the basic mechanisms of chemoprotection might be similar to those in CRC. Therefore, this review is focused on colorectal tumours.

Section snippets

APC and the β-catenin-mediated oncogenic Wnt pathway

Similar to other solid tumours, mutations at critical sites of oncogenes and/or tumour-suppressor genes combined with DNA-microsatellite instability and disturbed function of DNA-mismatch-repair genes underlie the pathogenesis of sporadic and hereditary forms of CRC [1]. The adenomatous polyposis coli (APC) tumour suppressor gene and its gene product APC appears to be the key player and is considered a ‘gatekeeper’ of the colonic epithelium [23]. Disturbed regulation of the oncogenic

APC and the β-catenin pathway – role of cancer stem cells

Mutations in the APC-gene and protein, respectively, result in a permanently activated state of β-catenin-induced gene transcription in the nucleus, including COX-2, as described above. Consequently, both aspirin and non-aspirin NSAIDs which inhibit tumorigenesis also interact with this signalling pathway [42], [43]. Colonic stem cells are the major target of interest. Because of their ability of self-renewal, their multipotency, i.e. the potential to generate differentiated cells of the tissue

Aspirin and non-aspirin NSAIDs – modes of action

In the complex pathogenesis of CRC, aspirin and NSAIDs have many effects that might contribute to chemoprevention of CRC. Two different modes of chemoprevention can be separated: COX-dependent and COX-independent actions. Both may act synergistically, perhaps at different levels of this multistep process [16] and there is some evidence for ‘replacement’ of APC function by NSAIDs. Thus, sulindac and indomethacin have been shown to inhibit tumorigenesis through inhibition of PPARdelta, a gene

Non-COX- related antitumour actions of aspirin and NSAIDs

Several lines of evidence suggest that COX-2 independent actions may also affect apoptosis and cell proliferation in CRC and are sensitive to aspirin and non-aspirin NSAIDs. Not all human colon cancer cells express COX-2 and produce prostaglandins [10], [18]. Nevertheless, the potency of aspirin, salicylate and NSAIDs to inhibit proliferation and induce apoptosis in COX-2 negative colon cancer cells is similar to that in COX-2- expressing cells [18], [19], [77]. This corresponds to inhibition

Practice points

Aspirin and non-aspirin NSAIDs, such as sulindac or celecoxib are potential candidates for long-term pharmacological prevention of CRC. Currently, aspirin appears to be the most promising drug, also because of its concomitant antiplatelet effects. These are not shared with non-aspirin NSAIDs which rather bear a prothrombotic risk.

The beneficial effect of aspirin are somewhat counterbalanced by an increased bleeding tendency, however the CRC-risk population of aged people might additionally

Research agenda

There is a clear need for a more precise definition of the cellular targets of primary pharmacological interest, including the relative contributions of COX-2-dependent and -independent actions to the overall therapeutic effect. Fresh insights into tumour pathogenesis, specifically the role of cancer stem cells, will help to optimize the pharmacological approaches.

Currently unsolved questions are the minimum duration of treatment, the optimum dosage, specifically in case of aspirin and the

Conflict of interest statement

None.

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