Use of phosphodiesterase 5 (PDE5) inhibitors (commonly used to treat erectile dysfunction) is associated with a 35% reduction in risk of colorectal cancer (CRC) among male patients with benign colorectal neoplasms, researchers report in the September issue of Gastroenterology. The decreased risk of CRC was associated with an increased cumulative dose of PDE5 inhibitor use.
Colon polyps can develop into CRC, and the risk of CRC is increased among patients who received polypectomy during colonoscopies, compared to individuals without polyps. Researchers have looked for agents that might reduce risk of CRC, especially in patients with colon polyps. Clopidogrel and low-dose aspirin, together or alone, reduce the risk of CRC by 20% to 30%, but other chemopreventive agents are needed.
Phosphodiesterases (PDEs) are a group of metallophosphohydrolases that block second messenger signaling related to cyclic adenosine monophosphate and cyclic guanosine monophosphate (cGMP). PDE5 promotes the cGMP-related signaling pathway that controls proliferation, migration, differentiation, and apoptosis of intestinal cells. PDE5 is overexpressed in human CRC cell lines and in colon adenomas and adenocarcinomas compared with normal colonic mucosa.
PDE5 inhibitors were originally used as a therapy for angina pectoris and were subsequently repurposed for treatment of erectile dysfunction and pulmonary arterial hypertension. However, some studies have shown that PDE5 inhibitors have anticancer activity and can prevent colorectal carcinogenesis. A range of selective PDE5 inhibitors with fewer adverse effects has been developed, including sildenafil, tadalafil, and vardenafil. Sildenafil (the most commonly used PDE5 inhibitor) inhibited polyp formation and tumorigenesis in APCMin/+ mice.
Wuqing Huang et al investigated whether use of PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) was associated with a reduced risk of CRC among male patients diagnosed with benign colorectal neoplasm, listed in the Swedish Hospital Discharge Register. The study did not include female patients because few women use PDE5 inhibitors.
A total of 4823 patients were prescribed PDE5 inhibitors during the study period; the incidence rate of CRC was 2.64 per 1000 person-years for men prescribed PDE5 inhibitors compared with 4.46 per 1000 person-years for men without a prescription for these drugs.
Huang et al found an inverse association between PDE5 inhibitor use and risk of CRC (adjusted hazard ratio, 0.65); the decreased risk of CRC was associated with an increased cumulative dose of PDE5 inhibitors. PDE5 prescription was associated with greater reduction in risk of advanced-stage CRC (adjusted hazard ratio, 0.61) than early-stage CRC (adjusted hazard ratio, 0.70), but the difference was not significant.
The association was consistent regardless of aspirin exposure (hazard ratios, 0.62 vs 0.64) or statin exposure (hazard ratios, 0.60 vs 0.65). After the authors excluded patients who had ever received polypectomy, PDE5 inhibitor use continued to be associated with a decreased risk of CRC, with an adjusted hazard ratio of 0.63.
How might PDE5 inhibitors prevent colorectal carcinogenesis? In an editorial that accompanies the article, Manol Jovani and Andrew Chan explain that PDE5 degrades cGMP. cGMP maintains epithelial homeostasis by organizing the crypt–villus structure and establishing barrier integrity (see figure). Low levels of cGMP activity increase intestinal cell proliferation, decrease differentiation of secretory lineage cells in the small intestine, and impair the epithelial barrier. This predisposes the intestinal epithelium to damage by chemicals, carcinogens, pathogens, and ionizing radiation, potentially leading to inflammation and cancer. PDE5 inhibitors therefore block these processes by keeping levels of cGMP high.
Although the findings of Huang et al provide evidence for the CRC chemopreventive effects for a commonly used class of drugs, Jovani and Chan et al state that prospective studies of PDE5 inhibitors and their effects on risk of CRC are needed to provide better evidence that these drugs might prevent colorectal carcinogenesis.