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Inhibition of lung tumorigenesis by NSAIDS: a working hypothesis
A Castonguay1, N Rioux, C Duperron
1Laboratory of Cancer Etiology and Chemoprevention, Faculty of Pharmacy, Laval University, Quebec City, Canada. andre.castonguay@pha.ulaval.ca
Abstract:
A 7-week treatment with the tobacco carcinogen NNK induced 8-10 lung adenomas per A/J mouse. NNK suppressed humoral and cellular immune responses and increased plasma PGE2 and LTB4 levels. This protocol is particularly suitable for testing NSAIDs and lipoxygenase inhibitors as cancer preventive agents. Sulindac and ASA inhibited lung tumorigenesis by 52 and 60%, respectively, attenuated the suppressive effect of NNK, and lowered the plasma PGE2 to basal levels. In contrast, naproxen neither inhibited lung tumorigenesis nor increased NNK-suppressed NK cell cytotoxicity. NSAIDs and lipoxygenase inhibitors had additive preventive efficacies against NNK-induced lung tumorigenesis. However, sulindac was not effective in preventing lung tumorigenesis induced by B[a]P, which lacks immunosuppressive activity. These results and those published by other investigators lead to the following hypothesis: Reactive intermediates derived from NNK interfere with the stimulation of the complex NF-kappa B/I kappa B. NF-kappa B is involved in the regulation of immune and inflammatory responses. The authors propose that NNK-derived intermediates induce the expression of COX-2 and lipoxygenase involved in NNK activation. This hypothesis provides a rationale for the lack of efficacy of naproxen to prevent tumorigenesis, to attenuate NNK-induced synthesis of PGE2, and to increase NK cell cytotoxicity. According to this hypothesis, PGE2 synthesis and induction of apoptosis contribute to varying degrees to the mechanism of cancer prevention.
Insights
Non-steroidal anti-inflammatory drugs (NSAIDs) and lipoxygenase inhibitors show promise in preventing lung cancer by counteracting tobacco carcinogen NNK. Sulindac and aspirin effectively inhibited NNK-induced lung tumors and immune suppression.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lung adenomas in A/J mice.
- NNK exposure suppresses immune responses and elevates plasma levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4).
Purpose of the Study:
- To evaluate the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) and lipoxygenase inhibitors in preventing NNK-induced lung tumorigenesis.
- To investigate the role of PGE2 and immune suppression in NNK-induced lung cancer and the mechanism of action of preventive agents.
Main Methods:
- A 7-week mouse model using NNK to induce lung adenomas.
- Treatment with NSAIDs (sulindac, aspirin, naproxen) and assessment of tumor incidence, immune cell cytotoxicity, and plasma mediator levels (PGE2, LTB4).
Main Results:
- Sulindac and aspirin significantly inhibited lung tumorigenesis (52% and 60%, respectively) and restored immune function.
- Naproxen failed to inhibit tumorigenesis or improve NK cell cytotoxicity, despite reducing PGE2.
- Combined NSAIDs and lipoxygenase inhibitors demonstrated additive preventive effects.
Conclusions:
- NSAIDs and lipoxygenase inhibitors can prevent NNK-induced lung tumorigenesis, potentially by modulating immune responses and inflammatory mediators.
- The efficacy of these agents may depend on their ability to counteract NNK's immunosuppressive effects and influence pathways involving NF-kappa B, COX-2, and lipoxygenase.
- PGE2 synthesis and apoptosis induction are proposed mechanisms for cancer prevention by these agents.
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