A Non-Systemic Phosphodiesterase-5 Inhibitor Suppresses Colon Proliferation in Mice

Abstract

Phosphodiesterase-5 inhibitors (PDE5i) are under investigation for repurposing for colon cancer prevention. A drawback to conventional PDE5i are their side-effects and drug–drug interactions. We designed an analog of the prototypical PDE5i sildenafil by replacing the methyl group on the piperazine ring with malonic acid to reduce lipophilicity, and measured its entry into the circulation and effects on colon epithelium. This modification did not affect pharmacology as malonyl-sildenafil had a similar IC50 to sildenafil but exhibited an almost 20-fold reduced EC50 for increasing cellular cGMP. Using an LC-MS/MS approach, malonyl-sildenafil was negligible in mouse plasma after oral administration but was detected at high levels in the feces. No bioactive metabolites of malonyl-sildenafil were detected in the circulation by measuring interactions with isosorbide mononitrate. The treatment of mice with malonyl-sildenafil in the drinking water resulted in a suppression of proliferation in the colon epithelium that is consistent with results previously published for mice treated with PDE5i. A carboxylic-acid-containing analog of sildenafil prohibits the systemic delivery of the compound but maintains sufficient penetration into the colon epithelium to suppress proliferation. This highlights a novel approach to generating a first-in-class drug for colon cancer chemoprevention.

cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment

“…However, phosphodiesterases (PDEs) inhibitors, which prevent cAMP or cGMP hydrolysis and thereby elevate cAMP/cGMP levels, are developed for the treatment of obstructive respiratory diseases, neuroinflammation, ischemia/reperfusion injury, atopic dermatitis, erectile dysfunction, depression and hypertension [ 13 – 15 ]. Preclinical studies demonstrate that PDE inhibitors may have tumor-suppressive effects, especially when combined with chemotherapeutic agents [ 16 , 17 ]. The present review updates recent advances in cAMP signaling, and discusses the complex roles of cAMP signaling in the TME.…”