Effect of Intermittent Versus Continuous Low-Dose Aspirin on Nasal Epithelium Gene Expression in Current Smokers: A Randomized, Double-Blinded Trial

Abstract

A chemopreventive effect of aspirin (ASA) on lung cancer risk is supported by epidemiologic and preclinical studies. We conducted a randomized, doubleblinded study in current heavy smokers to compare modulating effects of intermittent versus continuous low-dose ASA on nasal epithelium gene expression and arachidonic acid (ARA) metabolism. Fifty-four participants were randomized to intermittent (ASA 81 mg daily for one week/placebo for one week) or continuous (ASA 81 mg daily) for 12 weeks. Lowdose ASA suppressed urinary prostaglandin E2 metabolite (PGEM; change of À4.55 AE 11.52 from baseline 15.44 AE 13.79 ng/mg creatinine for arms combined, P ¼ 0.02), a surrogate of COX-mediated ARA metabolism, but had minimal effects on nasal gene expression of nasal or bronchial gene-expression signatures associated with smoking, lung cancer, and chronic obstructive pulmonary disease. Suppression of urinary PGEM correlated with favorable changes in a smoking-associated gene signature (P < 0.01). Gene set enrichment analysis (GSEA) showed that ASA intervention led to 1,079 enriched gene sets from the Canonical Pathways within the Molecular Signatures Database. In conclusion, low-dose ASA had minimal effects on known carcinogenesis gene signatures in nasal epithelium of current smokers but results in wide-ranging genomic changes in the nasal epithelium, demonstrating utility of nasal brushings as a surrogate to measure gene-expression responses to chemoprevention. PGEM may serve as a marker for smoking-associated gene-expression changes and systemic inflammation. Future studies should focus on NSAIDs or agent combinations with broader inhibition of pro-inflammatory ARA metabolism to shift gene signatures in an anti-carcinogenic direction.

Effect of Low-dose and Standard-dose Aspirin on PGE2 Biosynthesis Among Individuals with Colorectal Adenomas: A Randomized Clinical Trial

“…© 2020 American Association for Cancer cancerpreventionresearch.aacrjournals.org Downloaded from significant inhibition, irrespective of dose, was achieved here in a much shorter timeframe. Furthermore, our results are consistent with a randomized clinical trial in current heavy smokers (n ¼ 54) that demonstrated low-dose daily or intermittent aspirin reduced urinary PGE-M from baseline (31). Beyond urinary PGE-M, we also demonstrate that the change in serum PGE 2 measured by immunoassay appears correlated with the change in urinary PGE-M, offering another potential blood-based biomarker that may be conducive to implementation in clinical settings.…”

Head and neck squamous cell carcinoma

“…Modern trials of chemoprevention of tobacco-related cancers now focus on the cytoprotective, anti-inflammatory or immunomodulatory potential of repurposed pharmaceutical and nutraceutical compounds that are known to be well-tolerated during prolonged exposure. Ongoing secondary prevention trials include the evaluation of aspirin and other NSAIDs to reduce cyclooxygenase 2 (COX2) signalling 173 ; the study of metformin, an anti-hyperglycaemic biguanide that might block mTOR signalling in transforming epithelial cells 174 ; and trials of 'green chemoprevention' agents derived from cruciferous vegetables rich in isothiocyanates, which are thought to induce carcinogen detoxification and, possibly, innate immunity 175,176 .…”

Randomised clinical study: oral aspirin 325 mg daily vs placebo alters gut microbial composition and bacterial taxa associated with colorectal cancer risk

“…PGE‐M is an inflammatory biomarker shown to be increased in CRC 23‐25 . Urinary PGE‐M levels are reduced in aspirin users because PGE‐M reflects the production of systemic PGE2, which is suppressed by aspirin 26‐28 . Pre‐post treatment change in PGE‐M levels not only allowed us to estimate the correlation between changes in PGE‐M and gut bacteria due to aspirin intake, but also to check for compliance with aspirin intake.…”