The cGMP signaling pathway regulates homeostasis in the colon epithelium and has been implicated in the suppression of colorectal cancer. Exisulind is a weak phosphodiesterase-5 (PDE5) inhibitor that was previously shown to reduce polyp formation in familial adenomatous polyposis (FAP) patients. Despite this validation of PDE5 as a therapeutic target, the failure of Exisulind due to toxicity halted further trials of cGMP elevating agents. The present study tested the effect of the PDE5 inhibitor sildenafil, and the receptor guanylyl-cyclase C (GCC) agonist linaclotide on tumorigenesis in the ApcMin/+ mouse model of colon cancer. Administration of either sildenafil or linaclotide to both wild type and ApcMin/+ mice caused dramatic effects on homeostasis that included reduced proliferation and increased goblet cell differentiation. With treatment beginning at 4 weeks, sildenafil and linaclotide caused a 50% and 67% (respectively) reduction in the number of polyps per mouse. Furthermore, the polyps in sildenafil and linaclotide treated animals exhibited a reduced proliferative index and increased mucus density compared to polyps from untreated mice. The mean polyp size was not changed by treatment with either drug. In support of a tumor-suppressive role for cGMP signaling in the intestine, the ApcMin/+ mice showed reduced levels of endogenous GCC agonists in the intestinal mucosa compared to wild type animals. This suggests that part of the tumor preventative effects observed here could be due to compensation for this deficit by augmenting cGMP signaling with PDE5 inhibitors or GCC agonists. While the tumor suppressive mechanism is not fully understood, the results presented here demonstrate in a preclinical model, that increasing intestinal cGMP levels by targeting PDE5 or GCC may be a viable chemoprevention strategy for human FAP patients.
Citation Format: Sarah K. Sharman, Bianca N. Islam, Yali Hou, Allison Bridges, Nagendra Singh, Subbaramiah Sridhar, Frankin G. Berger, Darren D. Browning. Sildenafil suppresses tumorigenesis in ApcMin/+ mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2226. doi:10.1158/1538-7445.AM2017-2226