Mechanisms of nonsteroidal anti-inflammatory drugs in cancer prevention
Introduction
Recent secondary meta-analyses of large randomized clinical trials [1], [2], [3], [4], [5], [6], [7], [8] provide strong evidence for the cancer preventive effects of aspirin in reducing the incidence [9], mortality [10], and metastasis [10] of gastrointestinal and other cancers, especially adenocarcinomas. These data were recently reviewed in other publications [3], [4], [6], [8], [9], [10], [11]. Although various potential mechanisms may be responsible for aspirin’s preventive effects, the primary molecular pathway receiving general acceptance involves prostaglandins. Additional mechanisms are beginning to gain recognition, while others remain unknown since aspirin covalently acetylates many different molecules, which may serve as possible targets (Table 1) [12], [13], [14]. New insights into the mechanisms of aspirin’s action(s) may also be realized with recent advances in technology [15], [16], [17]. Hence, this article attempts to outline the most plausible mechanisms and supportive evidence underlying the cancer preventive efficacy of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs).
Aspirin is among the most successful drugs in history. It also serves as a key example of a commonly used anti-inflammatory drug with significant cancer preventive benefits. Thus, although aspirin is currently recommended for secondary prevention of cardiovascular disease (CVD) [18]; it may also be used for primary prevention in specific subsets of patients whose risk of serious bleeding does not outweigh the benefits estimated by the CVD indication [18], [19]. Analysis of 51 randomized controlled trials (RCTs) showed strong evidence that aspirin reduced cancer-associated mortality and prevented CVD when used daily (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76–0.96; P = .008) [10]. Overall, this beneficial effect was enhanced after 5 years (OR, 0.63; 95% CI, 0.49–0.82; P = .0005). Six trials also showed reduced cancer incidence after 3 years of use (OR, 0.76; 95% CI, 0.66–0.88; P = .0003). The reduction was most pronounced for gastrointestinal cancers, with a hazard ratio (HR) of 0.46 (95% CI, 0.27–0.77; P = .003), and was statistically significant for esophagus, colon, and lung cancers. All cancer preventive effects, including effects on incidence, mortality, and metastasis, increased with scheduled trial-treatment duration. Importantly, all case-fatality from major extra cranial bleeds was lower in aspirin than controls (OR, 0.32, 95% CI, 0.12–0.83; P = .009), suggesting a favorable risk:benefit ratio. Observational studies have also demonstrated reductions in cancer incidence [20], especially for cancers of the gastrointestinal tract, as well as for cancer-related [21], [22], [23] and all-cause mortality [21], [22], [24].
Earlier evidence that NSAIDs and aspirin prevent cancer came from multiple clinical trials involving short-term aspirin use at varying doses that produced a favorable outcome against colorectal adenomas. For example, in patients with a prior history of colorectal cancer (CRC) [25] or colorectal adenomas [26], [27], patients taking aspirin had a reduction in new adenomas when compared to the aspirin-free subset. The Colorectal Adenoma/Carcinoma Prevention Programme (CAPP) trial found that the long-term effects of aspirin using an intent-to-treat analysis for CRC indicated an HR of 0.63 (95% CI, 0.35–1.13; P = .12) in a specialized population with hereditary CRC (Lynch syndrome) [28].
In addition to aspirin, other NSAIDs and cyclooxygenase inhibitors (COXIBs) exhibited efficacy in CRC prevention trials. For example, celecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2), inhibited adenoma formation in high-risk patients with familial adenomatous polyposis (FAP) [29] and in patients following polypectomy [30], [31]. However, due to the cardiovascular toxicity observed in cancer prevention trials, rofecoxib and some other COX-2-selective inhibitors were pulled off the market [32], [33], [34] and although effective, those remaining on the market are not currently considered appropriate for cancer prevention purposes. Even with these setbacks, promising cancer preventive efficacy was observed in a phase III trial in which individuals with a history of adenomas were randomized to the NSAID sulindac used in combination with difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor. In those receiving the combination, both recurrent (relative risk [RR], 0.30; 95% CI, 0.18–0.49; P <.001) and advanced adenomas (RR, 0.085; 95% CI, 0.011–0.65; P <.001) were significantly and markedly reduced compared to placebo [35]. When considered together, these studies strongly suggest an overall role for aspirin and other NSAIDs as a class of drugs for reducing colon cancer risk. Key observations from recent analyses are summarized below:
- 1.
Adequate evidence shows a reduction in the incidence and mortality of a range of cancers associated with aspirin/NSAID use, especially in the gastrointestinal tract, with the strongest evidence for esophageal adenocarcinoma (30%–50%) and colorectal cancer (25–35%).
- 2.
Good evidence shows a reduction in stomach cancer (25%–40%); however, there is a much smaller effect on breast, prostate and lung cancer prevention.
- 3.
Little or no effect appears in existing data on other major cancer sites including pancreatic, endometrial, and hematopoietic tumors.
- 4.
The overall effect of regular long-term use of aspirin is a 20%–25% reduction in cancer incidence and mortality; the effect on incidence is not apparent until after 3 years of use; the effect on mortality is not apparent until after 5 years of use.
- 5.
Aspirin reduces the incidence of cardiovascular events by 15%–20%, both in the general population and in high-risk groups. However, with increasing awareness of risk factors and the wide range of effective agents available for the high-risk individuals, use of aspirin in the general population does not have a major impact on cardiovascular mortality.
- 6.
Not only is the risk of peptic ulcer and gastrointestinal (GI) bleeding age-dependent, but the seriousness of the outcome (proportion of fatal events) is also much greater in older individuals. The major risk of aspirin use (ie, GI bleeding), is associated with much less morbidity and lower mortality among individuals younger than 65 years.
- 7.
Overall mortality is reduced in aspirin users.
Despite this progress and decades of research, the precise mechanisms contributing to NSAIDs’ and aspirin’s efficacy in lowering cancer incidence, progression, and metastasis, as well as reducing effects on cancer-associated mortality, remain unclear. Here we outline several leading mechanisms and pathways that may be implicated in the overall benefit seen with aspirin and NSAIDs. Furthermore, in view of the biologic complexities and signaling pathways involved in cancer development, several lines of evidence also suggest that multiple mechanisms are responsible for its broad effects on carcinogenesis.
Section snippets
2. Possible mechanisms for cancer prevention using NSAIDs and/or aspirin
Ample evidence from various sources supports inflammation as playing a role in the initiation, progression, and development of cancer. Inflammation is a hallmark of cancer (see Ryan and Faupel-Badger, this issue) [36], [37]; therefore, it is quite possible that simply targeting anti-inflammatory processes might reduce cancer incidence and cancer-associated mortality. Many cancers are associated with chronic inflammatory diseases (eg, inflammatory bowel disease, Crohn’s and colitis, both viral
3. Aspirin and NSAIDs for cancer prevention
Aspirin and NSAIDs have been extensively tested preclinically in mice and rats after either genetic or chemical induction of carcinogenesis. Briefly, the experience with aspirin has been mixed where mice show somewhat different pharmacokinetics and efficacy, where these animals seem to show dose dependency as well as efficacy at much higher doses than equivalent doses in humans [139], [197], [211]. Regardless of some differences in the dose dependency or actual translation to human cancer
4. Summary
The continued study of the effect of NSAIDs on cancer progression strengthens the notion that COX-dependent mechanisms are primarily involved in this process. Additional studies are revealing that COX-independent pathways may also be involved in prevention of cancer. This point is critical and raises a few major questions: COX-1/2 play key roles in carcinogenesis, and we continue to learn about other valuable targets, but how do we prioritize their importance? And, although COX-2
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