Sildenafil suppresses inflammation-driven colorectal cancer in mice

Intestinal cyclic guanosine monophosphate (cGMP) signalingregulatesepithelialhomeostasisandhasbeenimplicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5(PDE5)inhibitorsildenafiltoprevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS)inflammation-drivencolorectalcancermodel. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against dextran-sulfate sodium (DSS)-induced barrierdysfunction. In micetreated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared with untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared with polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cellinfiltration and reduced expression of iNOS, IFNg, and IL6 compared with untreated controls. Most of the protection conferred by sildenafil was during the initiation stage of carcinogenesis (38% reduction in multiplicity). Administration of sildenafil during the later promotion stages did not affect multiplicity but had a similar effect on the polyp phenotype, including increased mucus production, and reduced proliferation and inflammation. In summary, the results demonstrate that oral administration ofsildenafilsuppressespolypformationandinflammation in mice treated with AOM/DSS. This validation of PDE5 as a target highlights the potential therapeutic value of PDE5 inhibitors for the prevention of colitis-driven colon cancer in humans.