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Cancer prevention: a new era beyond cyclooxygenase-2
1Division of Cancer Prevention, Department of Medicine, SUNY at Stony Brook, Stony Brook, NY 11794-8160, USA. basil.rigas@sunysb.edu
Abstract:
The seminal epidemiological observation that nonsteroidal anti-inflammatory drugs (NSAIDs) prevent colon and possibly other cancers has spurred novel approaches to cancer prevention. The known inhibitory effect of NSAIDs on the eicosanoid pathway prompted studies focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. Their efficacy in the prevention of sporadic colon and other cancers remains unknown; one COX-2 inhibitor has been withdrawn because of side effects, and there are concerns about whether these effects are class-specific. There is evidence to suggest that COX-2 may not be the only or ideal eicosanoid pathway target for cancer prevention. Six sets of observations support this notion: the relatively late induction of COX-2 during carcinogenesis; the finding that NSAIDs may not require inhibition of COX-2 for their effect; the modest effect of coxibs in cancer prevention; that currently available coxibs have multiple non-COX-2 effects that may account for at least some of their efficacy; the possibility that concurrent inhibition of COX-2 in non-neoplastic cells may be harmful; and the possibility that COX-2 inhibition may modulate alternative eicosanoid pathways in a way that promotes carcinogenesis. Given the limitations of COX-2-specific inhibitors and the biological evidence mentioned above, we suggest that targets other than COX-2 should be pursued as alternative or complementary approaches to cancer prevention.
Insights
Nonsteroidal anti-inflammatory drugs (NSAIDs) show promise in preventing colon cancer by targeting the eicosanoid pathway. However, cyclooxygenase-2 (COX-2) inhibitors may not be the sole effective target for cancer prevention.
Area of Science:
- Oncology
- Pharmacology
- Epidemiology
Background:
- Epidemiological studies suggest nonsteroidal anti-inflammatory drugs (NSAIDs) possess cancer-preventive properties, particularly for colon cancer.
- NSAIDs' mechanism is linked to the eicosanoid pathway, specifically cyclooxygenase (COX) enzymes and their products like prostaglandin E2 (PGE2).
- Overexpression of COX-2 is observed in various cancers, leading to clinical trials investigating COX-2 inhibitors for cancer prevention and treatment.
Purpose of the Study:
- To evaluate the efficacy and safety of COX-2 inhibitors in sporadic cancer prevention.
- To explore alternative or complementary targets within the eicosanoid pathway for cancer prevention.
- To address concerns regarding the class-specific effects and potential harms of COX-2 inhibition.
Main Methods:
- Review of epidemiological data on NSAIDs and cancer.
- Analysis of preclinical and clinical studies on COX-2 inhibitors (coxibs).
- Evaluation of biological evidence regarding COX-2 induction and function in carcinogenesis.
Main Results:
- The efficacy of coxibs in preventing sporadic colon and other cancers remains uncertain.
- One COX-2 inhibitor was withdrawn due to adverse effects, raising concerns about class-specific toxicity.
- Evidence suggests COX-2 may not be the only or ideal target, as NSAIDs might act independently of COX-2 inhibition, and coxibs have non-COX-2-related effects.
Conclusions:
- COX-2 specific inhibitors have limitations and potential risks, including possible harm in non-neoplastic cells and unintended modulation of other pathways.
- Alternative or complementary targets beyond COX-2 should be investigated for more effective and safer cancer prevention strategies.
- The complex role of COX-2 in carcinogenesis warrants a broader approach to developing novel cancer prevention therapies.
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