Abstract
Celecoxib, a nonsteroidal anti-inflammatory drug that selectively targets cyclooxygenase-2, is a promising cancer chemopreventive agent. However, safety concerns have been raised in clinical trials evaluating its ability to prevent colorectal adenomas. The rationale for the herein reported studies was to analyze genomic and epigenetic end-points aimed at investigating both the chemopreventive properties of celecoxib towards cigarette smoke-associated molecular alterations and its possible adverse effects. We carried out three consecutive studies in mice treated with either smoke and/or celecoxib. Study 1 investigated early DNA alterations (DNA adducts, oxidative DNA damage, and systemic genotoxic damage) and epigenetic alterations (expression of 1,135 microRNAs) in lung and blood of Swiss H mice; Study 2 evaluated the formation of DNA adducts in lung, liver, and heart; and Study 3 evaluated the expression of microRNAs in 10 organs and 3 body fluids of ICR (CD-1) mice. Surprisingly, the oral administration of celecoxib to smoke-free mice resulted in the formation of DNA adducts in both lung and heart and in dysregulation of microRNAs in mouse organs and body fluids. On the other hand, celecoxib attenuated smoke-related DNA damage and dysregulation of microRNA expression. In conclusion, celecoxib showed pleiotropic properties and multiple mechanisms by counteracting the molecular damage produced by smoke in a variety of organs and body fluids. However, administration of celecoxib to non-smoking mice resulted in evident molecular alterations, also including DNA and RNA alterations in the heart, which may bear relevance in the pathogenesis of the cardiovascular adverse effects of this drug.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used worldwide for the treatment of inflammation-related diseases
Study 1 investigated early DNA alterations (DNA adducts, oxidative DNA damage, and systemic genotoxic damage) and epigenetic alterations in lung and blood of Swiss H mice; Study 2 evaluated the formation of DNA adducts in lung, liver, and heart; and Study 3 evaluated the expression of microRNAs in 10 organs and 3 body fluids of ICR (CD-1) mice
We showed that administration of celecoxib after weanling to Swiss H mice, which had been exposed to mainstream cigarette smoke (MCS) since birth and thereafter kept in filtered air for an additional 3.5 months, results in a variety of protective effects towards MCS-related carcinogenesis [18]
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used worldwide for the treatment of inflammation-related diseases. Among other applications, these agents provide a promising approach to the prevention of cancer, including smoking-associated cancers [1]. These agents provide a promising approach to the prevention of cancer, including smoking-associated cancers [1] The rationale for such a strategy is that chronic inflammation plays a key role at different stages of the carcinogenesis process [2, 3] and is crucial in tobacco smoke carcinogenesis [4]. NSAIDs interfere with the metabolism of arachidonic acid, a ω-6 essential fatty acid that is the substrate for different enzyme systems, including cyclooxygenases (COX), lipoxygenases, and cytochromes P450. COX-2 is the inducible isoform, expressed in response to certain stimuli such as mitogens, cytokines and growth factors, which has a proinflammatory function [5]
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