Sildenafil Suppresses Inflammation-Driven Colorectal Cancer in Mice

Abstract

Intestinal cyclic guanosine monophosphate (cGMP) signaling regulates epithelial homeostasis and has been implicated in the suppression of colitis and colon cancer. In this study, we investigated the cGMP-elevating ability of the phosphodiesterase-5 (PDE5) inhibitor sildenafil to prevent disease in the azoxymethane/dextran sulfate sodium (AOM/DSS) inflammation-driven colorectal cancer model. Treatment of mice with sildenafil activated cGMP signaling in the colon mucosa and protected against DSS-induced barrier dysfunction. In mice treated with AOM/DSS, oral administration of sildenafil throughout the disease course reduced polyp multiplicity by 50% compared to untreated controls. Polyps that did form in sildenafil treated mice were less proliferative and more differentiated compared to polyps from untreated mice, but apoptosis was unaffected. Polyps in sildenafil treated mice were also less inflamed; they exhibited reduced myeloid-cell infiltration, and reduced expression of iNOS, IFNγ, and IL-6 compared to 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 of sildenafil suppresses polyp formation and inflammation 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.

Phosphodiesterase 10A is overexpressed in lung tumor cells and inhibitors selectively suppress growth by blocking β-catenin and MAPK signaling

“…We detected PDE5 in two of five NSCLC cell lines examined, but the levels were comparable to NHAEC. The PDE5 selective inhibitor, sildenafil has also been reported to inhibit tumorigenesis in an inflammation-driven model of colon cancer, which suggests a potentially important role of PDE5 in tumorigenesis [ 47 ]. However, the abundance of PDE10 in tumor cells may limit the sensitivity of tumor cells to PDE5 inhibitors, whereby combined treatment with PDE5 and PDE10 inhibitor or treatment with a dual PDE5/10 inhibitor may hold greater promise as a therapeutic strategy [ 33 , 48 ].…”

Phosphodiesterase type 5 and cancers: progress and challenges

“…In clinical studies, exisulind prevented colorectal polyp formation in patients with familial adenomatous polyposis (FAP) over 24 months [ 243 , 244 ]. Moreover, it has been demonstrated that exisulind inhibited azoxymethane-induced colon carcinogenesis in rats [ 201 ] and sildenafil suppressed polyp formation and inflammation in mice treated with azoxymethane/dextrane sulfate sodium [ 245 ], highlighting the chemopreventive role of PDE5 inhibition [ 246 ].…”

Use of Phosphodiesterase 5 Inhibitors Is Associated With Lower Risk of Colorectal Cancer in Men With Benign Colorectal Neoplasms

“…First, the immunomodulatory effects of PDE5 inhibitors have been suggested to be associated with an anticancer effect, which was first shown by Serafini et al 35 and then further confirmed by other researchers in studies conducted on mice. 17,36,37 Second, Zhu et al 38 and Wang et al 39 conducted experiments in vitro and found that PDE5 inhibitors induced apoptosis, inhibited cell proliferation, and promoted differentiation in colonic epithelium by activating the cGMP/ protein kinase G II pathway. 38,39 In addition, a range of results in vitro showed that PDE5 was related to increased cancer treatment sensitivity through inhibiting resistance to some commonly used cancer drugs (5-fluorouracil and doxorubicin) or enhancing tumor permeability via effects on the blood-brain barrier.…”