Modulation of genomic and epigenetic end-points by celecoxib

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.

Modulation of smoke-induced DNA and microRNA alterations in mouse lung by licofelone, a triple COX-1, COX-2 and 5-LOX inhibitor

“…In agreement with the results of previous studies (21,22,(37)(38)(39)(40)(41), exposure of mice to MCS resulted in an evident oxidative DNA damage in lung. Moreover, high levels of bulky DNA adducts were detectable in the form of DRZ at 32 P postlabeling, which is typical for exposure to complex mixtures.…”

“…A similar situation occurred in mice treated with the other nonselective NSAID naproxen, in which another miR-30b homologue (miR-30c) was significantly more expressed in MCS-exposed mice treated with the drug that were free of adenomas than in those bearing adenomas (22). On the other hand, the miRNAs upregulated by the selective COX-2 inhibitor celecoxib in the lung of MCS-exposed Swiss H mice were different from those upregulated by licofelone under identical experimental conditions (21). As to miR-125b, this miRNA having multiple functions was upregulated both in the lung of Swiss H mice exposed for 10 weeks to MCS since birth and treated with licofelone after weaning (present study) and in the lung of 2-month old ICR(CD-1) mice exposed to MCS for 8 weeks and receiving celecoxib during the same period (21).…”

“…On the other hand, the miRNAs upregulated by the selective COX-2 inhibitor celecoxib in the lung of MCS-exposed Swiss H mice were different from those upregulated by licofelone under identical experimental conditions (21). As to miR-125b, this miRNA having multiple functions was upregulated both in the lung of Swiss H mice exposed for 10 weeks to MCS since birth and treated with licofelone after weaning (present study) and in the lung of 2-month old ICR(CD-1) mice exposed to MCS for 8 weeks and receiving celecoxib during the same period (21).…”

“…Among anti-inflammatory drugs, we investigated the cancerprevention ability of 4 NSAIDs, including the selective COX-2 inhibitor celecoxib (19), the COX-1 and COX-2 inhibitors aspirin and naproxen (20), and the triple COX-1, COX-2, and 5-LOX inhibitor licofelone (19). In addition, we evaluated the properties of celecoxib (21), naproxen and aspirin (22) to modulate MCSrelated alterations of genomic and epigenetic nature in mice.…”

Cytokinesis-block micronucleus assay of celecoxib and celecoxib derivatives

“…Incubation of whole blood with celecoxib even reduced the induction of micronuclei caused by ionising radiation in a cytokinesis-block micronucleus test in human lymphocytes [ 22 ]. In contrast, another study demonstrated a more complicated relation between celecoxib and DNA damage: While accumulation of DNA-adducts was observed in lung and heart of smoke-free mice after exposure to celecoxib, smoke-induced DNA-damage was reduced after treatment with celecoxib, that made the authors propose multiple mechanisms for celecoxib to interact with DNA [ 23 ].…”