Bioactivity of Oral Linaclotide in Human Colorectum for Cancer Chemoprevention

Abstract

Guanylate cyclase C (GUCY2C) is a tumor suppressing receptor silenced by loss of expression of its luminocrine hormones guanylin and uroguanylin early in colorectal carcinogenesis. This observation suggests oral replacement with a GUCY2C agonist may be an effective targeted chemoprevention agent. Linaclotide is an FDA approved oral GUCY2C agonist formulated for gastric release, inducing fluid secretion into the small bowel to treat chronic idiopathic constipation. The ability of oral linaclotide to induce a pharmacodynamic response in epithelial cells of the colorectum in humans remains undefined. Here, we demonstrate that administration of 0.87 milligrams of oral linaclotide daily for 7 days to healthy volunteers, after oral colon preparation with polyethylene glycol solution (MoviPrep), activates GUCY2C, resulting in accumulation of its product cyclic (c)GMP in epithelial cells of the cecum, transverse colon, and distal rectum. GUCY2C activation by oral linaclotide was associated with homeostatic signaling, including phosphorylation of vasodilator-stimulated phosphoprotein and inhibition of proliferation quantified by reduced Ki67-positive epithelial cells. In the absence of the complete oral colonoscopy preparation, linaclotide did not alter cGMP production in epithelial cells of the colorectum, demonstrating that there was an effect related to the laxative preparation. These data show that the current FDA-approved formulation of oral linaclotide developed for small bowel delivery to treat chronic idiopathic constipation is inadequate for reliably regulating GUCY2C in the colorectum to prevent tumorigenesis. The study results highlight the importance of developing a novel GUCY2C agonist formulated for release and activity targeted to the large intestine for colorectal cancer prevention.

ST-Producing E. coli Oppose Carcinogen-Induced Colorectal Tumorigenesis in Mice

“…Taken together, these observations suggest a pathophysiological hypothesis that guanylin loss silencing GUCY2C signaling is an essential step in colorectal tumorigenesis [ 15 ]. Moreover, it suggests the correlative therapeutic hypothesis that oral GUCY2C ligand replacement may be a tractable approach to prevent colorectal cancer in patients [ 16 ].…”

“…Moreover, they support the therapeutic hypothesis that colorectal cancer might be prevented by oral GUCY2C ligand replacement [ 9 , 11 , 15 ]. The immediate tractability of this therapeutic approach is underscored by the recent approval of linaclotide ( Linzess ™) and plecanatide ( Trulance ™), oral GUCY2C ligands approved for the treatment of chronic constipation syndromes [ 16 , 44 ].…”

“…Moreover, GUCY2C ligand replacement opposed mutational or carcinogen-induced intestinal carcinogenesis in mice [ 9 , 12 ]. In that context, GUCY2C ligand replacement is emerging as a novel paradigm for colorectal cancer chemoprevention [ 15 , 16 ].…”

Uroguanylin: a new actor in the energy balance movie

“…In this context, one novel therapeutic approach to cancer prevention would be treatment with an oral preparation of linaclotide, a synthetic 14-amino acid peptide that has more than 60% amino acid identity with guanylin and uroguanylin (Weinberg et al 2017). A secondary therapeutic approach has been proposed that comprises the oral administration of plecanatide, which acts via cGMP/GC-C signaling to mediate the downregulation of Wnt/b-catenin signaling within the colon, thereby delaying the progression of colorectal cancer.…”

APC-β-catenin-TCF signaling silences the intestinal guanylin-GUCY2C tumor suppressor axis

“…19 Silencing GUCY2C imposes an aberrant phenotype along that axis, characterized by reduced mitochondria, increased glycolysis, and decreased oxygen consumption, recapitulating the Warburg metabolic phenotype in tumors. 19 Moreover, silencing GUCY2C increases DNA oxidation and double strand breaks, mutagenesis induced by alkylating agents, and chromosomal instability 18,19 Guanylin is reduced, [25][26][27][28] while GUCY2C is conserved, [29][30][31] in colorectal adenomas and carcinomas in humans and mice.…”