title: 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 mg 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.Cancer Prev Res; 10(6); 345-54. ©2017 AACR.
authors.affiliation: Department of Medicine, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: David S
authors.initials: DS
authors.lastname: Weinberg
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jieru E
authors.initials: JE
authors.lastname: Lin
authors.affiliation: Mayo Foundation for Medical Education and Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Foster
authors.affiliation: Division of Cancer Prevention, NCI, NIH, Bethesda, Maryland.
authors.forename: Gary
authors.initials: G
authors.lastname: Della'Zanna
authors.affiliation: Division of Cancer Prevention, NCI, NIH, Bethesda, Maryland.
authors.forename: Asad
authors.initials: A
authors.lastname: Umar
authors.affiliation: Mayo Foundation for Medical Education and Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Drew
authors.initials: D
authors.lastname: Seisler
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kraft
authors.affiliation: Division of Gastroenterology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: David M
authors.initials: DM
authors.lastname: Kastenberg
authors.affiliation: Division of Gastroenterology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Leo C
authors.initials: LC
authors.lastname: Katz
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Limburg
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania. scott.waldman@jefferson.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Waldman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003106:Colon / Q000000981:diagnostic imaging / Q000187:drug effects*; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000517:prevention & control*; D006152:Cyclic GMP / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005768:Gastrointestinal Hormones / Q000378:metabolism; D000074268:Guanylyl Cyclase C Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D064368:Healthy Volunteers; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008840:Microfilament Proteins / Q000378:metabolism; D045265:Natriuretic Peptides / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011092:Polyethylene Glycols / Q000494:pharmacology; D000074261:Receptors, Enterotoxin / Q000378:metabolism*; D012007:Rectum / Q000000981:diagnostic imaging / Q000187:drug effects*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D005768:Gastrointestinal Hormones; D000074268:Guanylyl Cyclase C Agonists; D019394:Ki-67 Antigen; D008840:Microfilament Proteins; C520497:MoviPrep; D045265:Natriuretic Peptides; D010455:Peptides; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; C072685:guanylin; C084362:uroguanylin; D011092:Polyethylene Glycols; C000613654:GUCY2C protein, human; D000074261:Receptors, Enterotoxin; D006152:Cyclic GMP; C523483:linaclotide