Inhibition of human colon carcinoma cell growth by ammonia: a non-cytotoxic process associated with polyamine synthesis reduction

Ammonia, produced by bacterial degradation of unabsorbed and endogenous nitrogenous compounds, is found to be present at millimolar concentrations in the colon lumen. From in vivo animal experiments, this metabolite has been shown to alter colonic epithelial cell morphology and to increase compensat...

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Published in:Biochimica et biophysica acta Vol. 1624; no. 1; pp. 88 - 97
Main Authors: Mouillé, Béatrice, Delpal, Serge, Mayeur, Camille, Blachier, François
Format: Journal Article
Language:English
Published: Netherlands Elsevier B.V 05.12.2003
Subjects:
Ammonia
Ammonia - metabolism
Ammonium Chloride - pharmacology
Biogenic Polyamines - biosynthesis
Cell Cycle - drug effects
Cell Differentiation - drug effects
Cell Division - drug effects
Colon carcinoma cell
Colonic Neoplasms - drug therapy
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Glutamine - metabolism
HT29 Cells
Humans
Metabolism
Polyamine
Proliferation
Protein Biosynthesis
Putrescine - pharmacology
Ammonia
Polyamine
Proliferation
Colon carcinoma cell
Metabolism
ISSN:0304-4165, 0006-3002, 1872-8006
Online Access:Get full text
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Summary:Ammonia, produced by bacterial degradation of unabsorbed and endogenous nitrogenous compounds, is found to be present at millimolar concentrations in the colon lumen. From in vivo animal experiments, this metabolite has been shown to alter colonic epithelial cell morphology and to increase compensatory cell proliferation when present in excess. In this in vitro study, using the human colon adenocarcinoma HT-29 Glc −/+ cell line treated with increasing doses of NH 4Cl, we found that 20 mM NH 4Cl, a concentration close to that found in the large intestine lumen, was able to increase the volume of vacuolar lysosomes and to repress HT-29 Glc −/+ cell proliferation. This growth-inhibitory effect was not correlated with decrease of cell viability, with modification of cell differentiation and change of the cell distribution in the different cell cycle phases, thus indicating a proportional slowdown in all cell cycle phases. In contrast to what is found in healthy colonocytes, ammonia was not metabolized by HT-29 cells into carbamoyl-phosphate (carbamoyl-P) and citrulline, indicating that ammonia was likely acting on cells by itself. This agent was shown to markedly reduce cellular ornithine decarboxylase (ODC) activity resulting in a threefold decrease in the capacity of HT-29 cells to synthetize polyamines, these latter metabolites being strictly necessary for cell growth. The unexpected finding that ammonia is acting as an antimitotic agent against tumoral HT-29 colonic cells may be related to the inability of these cells to metabolize this compound.
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ISSN:0304-4165
0006-3002
1872-8006
DOI:10.1016/j.bbagen.2003.09.014