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.