uroguanylin and Chronic-Disease

Plecanatide (Trulance

Topics: Adult; Chronic Disease; Clinical Trials, Phase III as Topic; Constipation; Drug Approval; Gastrointestinal Agents; Humans; Molecular Structure; Natriuretic Peptides; United States

Chronic constipation (CC) is one of the most common functional gastrointestinal disorders. CC is estimated to affect up to 27% of the North American population. Although not life-threatening, CC can have profoundly negatively affects on quality of life and result in significant economic burden in terms of both direct and indirect healthcare costs. Possible etiologies for CC include alterations in gastrointestinal motility and secretion. Research efforts in CC have begun to identify multifactorial and often overlapping etiologies including abnormalities in myenteric neurons, alterations in neurotransmitters and their receptors, and incoordination of the muscles of the pelvic floor or anorectum. CC may be influenced by genetic predisposition, environmental factors and stress. In this article, the safety and efficacy of traditional and emerging therapies for CC are examined.

Topics: Analgesics, Opioid; Cathartics; Chloride Channel Agonists; Chronic Disease; Constipation; Drug Discovery; Gastrointestinal Motility; Humans; Motilin; Narcotic Antagonists; Natriuretic Peptides; Serotonin Agents

The peptide hormones guanylin and uroguanylin and their receptor, guanylate cyclase C (GC-C), are expressed in pancreatic duct cells. In colon cancer, guanylin peptides are shown to exert strong anti-tumor activity through the GC-C pathway. The objective of this study was to analyze the role of guanylin and uroguanylin in human pancreatic cancer.. Quantitative real-time polymerase chain reaction (QRT-PCR) was used to show the expression of guanylin, uroguanylin and GC-C in specimens of human pancreatic cancer, chronic pancreatitis donor and in pancreatic tumor cell lines. The presence of guanylins and GC-C in tumor cell lines and in pancreatic cancer tissues was shown by immunofluorescence and immunohistochemistry. The effect of guanylin and uroguanylin on cell cycle and cell death of pancreatic cancer cells was investigated by fluorescence activated cell sorter (FACS) analysis using annexin and propidium iodide. In addition, the growth inhibitory effect of guanylins on pancreatic cancer cells was assessed using the MTT assay.. Guanylin, uroguanylin and GC-C were expressed at mRNA and protein levels in pancreatic cancer and cancer cell lines. As shown by QRT-PCR, GC-C expression was significantly up-regulated in pancreatic cancer compared with that in healthy pancreatic tissues (p<0.00001) and chronic pancreatitis (p<0.05). Guanylin and uroguanylin were not up-regulated in pancreatic cancer. The MTT assay revealed significant inhibition of pancreatic cancer cell proliferation by uroguanylin in a dose-dependent fashion, whereas Panc1 and Capan1 cell lines were significantly inhibited already at the lowest uroguanylin concentration (2 nM, p<0.05).. Our data suggest therapeutic properties of uroguanylin in pancreatic cancer via GC-C-dependent mechanisms. In addition, determination of GC-C expression might be a useful marker for differentiation between pancreatic cancer and chronic pancreatitis.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; Cell Division; Cell Line, Tumor; Chronic Disease; Female; Gastrointestinal Hormones; Guanylate Cyclase; Humans; Male; Middle Aged; Natriuretic Peptides; Pancreas; Pancreatic Neoplasms; Pancreatitis; Polymerase Chain Reaction