GUT TARGETED PDE5 INHIBITORS SUPPRESS INTESTINAL CARCINOGENESIS IN MICE

Increasing cGMP in the intestinal epithelium is has been shown in both preclinical and clinical settings to have therapeutic effects on chronic constipation, enteric nociception, barrier dysfunction, and cancer. The only cGMP-elevating agents currently prescribed for intestinal diseases are guanylate-cyclase C (GC-C) agonists, that have diarrhea as an important side effect and do not reach the distal colon where most cancers arise. A growing body of evidence has shown that phosphodiesterase 5 inhibitors (PDE5i) can prevent colorectal cancer (CRC), but this class of drugs has numerous side effects and drug-drug interactions due to systemic delivery. To address this issue, we recently reported the development of a novel gut-targeted PDE5i (Mal-sild) that can suppress proliferation in the colon epithelium of mice without entering the circulation. The present study has tested whether long-term oral delivery of Mal-sild can suppress intestinal carcinogenesis in the ApcMIN mouse model. Mal-sild exhibited a low membrane permeability using Caco-2 barriers and was undetectable in the liver or peripheral circulation of mice after oral delivery. To determine whether Mal-sild could suppress intestinal carcinogenesis, ApcMIN/+ mice were provided the compound in drinking water between 4-14 weeks of age followed by analysis of tumor formation. Treated animals exhibited a 43% reduction in the number of intestinal polyps compared to controls but did not affect tumor size. Our results demonstrate that CRC prevention by PDE5i does not require systemic delivery and highlight Mal-sild as a novel gut-targeted drug for further development as a first in class chemoprevention agent for patients at high risk of developing CRC.