Abstract 1636: Enhancement of cyclic GMP production by guanylate cyclase-C agonists delays progression of colitis into colon cancer though downregulation of pro-inflammatory cytokines
Authors: Shailubhai Kunwar , Chang Wen-Chi , Masih Shet , Cooper Harry S. , Clapper Margie L. 
Published: August 2012

Abstract
Colon cancer is one of the most prevalent malignancies in the world; with an estimated 875,000 cases diagnosed worldwide; accounting for 8.5% of all new cancers. Patients with ulcerative colitis and Crohn's disease are at increased risk of developing colorectal cancer. It is believed that the persistent gastrointestinal (GI) inflammation may contribute to colorectal carcinogenesis. The cGMP signaling mediates anti-inflammatory effects of cellular molecules such as nitric oxide and hemeoxygenase-1. Therefore, therapies that induce cyclic GMP and cyclic AMP levels by inhibiting their degradation (phosphodiesterase inhibitors) exhibit good efficacy in murine models of ulcerative colitis. Activation of guanylate cyclase C (GC-C) by uroguanylin (UG), a peptide hormone produced in the GI tract lumen, results in enhanced production of cyclic GMP. Earlier we reported that UG expression is suppressed in human colon tumors and that the oral treatment with UG inhibited polyps formation in ApcMin/+ mice via a cGMP-mediated mechanism. Subsequently, we also reported that GC-C agonists (plecanatide and SP-333), highly potent analogs of UG, ameliorated GI inflammation in murine colitis models via downregulation of certain pro-inflammatory cytokines. Thus, we reasoned that GC-C agonists might also retard progression of colitis into colorectal tumors. Apc Min/+ mice were randomized to receive either powdered diet supplemented with or without plecanatide. DSS (4%) was administered in the drinking water for two cycles. Cycle 1 consisted of 4 days of DSS plus 17 days of water. Cycle 2 consisted of 3 days of DSS plus 18 days of water. Mice were sacrificed at 15 wks of age. The number of tumors per animal was counted for each segment of the colon. The mRNA levels of UG, GC-C, Ki-67 and protein levels of β-catenin within the colon were measured. Expression of cytokines was examined in explant cultures of colon. Both plecanatide and SP-333 were as effective as sulfasalazine or 5-ASA to inhibit DSS-induced inflammation in mice. Treatment with plecanatide reduced multiplicity of tumors within the colon, increased expression of protein kinase G-II (PKG-II) and decreased levels of Ki-67 and β-catenin. Expression of UG was reduced following DSS treatment but it was partially restored following treatment with plecanatide. In explant cultures, plecanatide reduced production of the pro-inflammatory cytokines such as IL-6, IL-17 and IL-23. These results suggest that anti-inflammatory and anti-carcinogenesis activities of plecanatide were mediated through downregulation of pro-inflammatory cytokines. This study opens a novel avenue for development of GC-C agonists as a new class of orally delivered, mucosally active, drug candidates for treatment of GI inflammatory diseases and IBD-associated colon cancer. Supported by NIH grant R21 CA133689 to KS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1636. doi:1538-7445.AM2012-1636