title: Effects of agmatine accumulation in human colon carcinoma cells on polyamine metabolism, DNA synthesis and the cell cycle.
abstract: Putrescine, spermidine and spermine are low molecular polycations that play important roles in cell growth and cell cycle progression of normal and malignant cells. Agmatine (1-amino-4-guanidobutane), another polyamine formed through arginine decarboxylation, has been reported to act as an antiproliferative agent in several non-intestinal mammalian cell models. Using the human colon adenocarcinoma HT-29 Glc(-/+) cell line, we demonstrate that agmatine, which markedly accumulated inside the cells without being metabolised, exerted a strong cytostatic effect with an IC50 close to 2 mM. Agmatine decreased the rate of L-ornithine decarboxylation and induced a 70% down-regulation of ornithine decarboxylase (ODC) expression. Agmatine caused a marked decrease in putrescine and spermidine cell contents, an increase in the N1-acetylspermidine level without altering the spermine pool. We show that agmatine induced the accumulation of cells in the S and G2/M phases, reduced the rate of DNA synthesis and decreased cyclin A and B1 expression. We conclude that the anti-metabolic action of agmatine on HT-29 cells is mediated by a reduction in polyamine biosynthesis and induction in polyamine degradation. The decrease in intracellular polyamine contents, the reduced rate of DNA synthesis and the cell accumulation in the S phase are discussed from a causal perspective.
authors.affiliation: Unité de Nutrition et Sécurité alimentaire, Institut National de la Recherche Agronomique, 78350 Jouy-en-Josas, France. Camille.Mayeur@jouy.inra.fr
authors.forename: Camille
authors.initials: C
authors.lastname: Mayeur
authors.forename: Géraldine
authors.initials: G
authors.lastname: Veuillet
authors.forename: Marie
authors.initials: M
authors.lastname: Michaud
authors.forename: Francis
authors.initials: F
authors.lastname: Raul
authors.forename: Hervé M
authors.initials: HM
authors.lastname: Blottière
authors.forename: François
authors.initials: F
authors.lastname: Blachier
mesh_terms: D000376:Agmatine / Q000493:pharmacokinetics / Q000494:pharmacology*; D001711:Biotransformation; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; D011073:Polyamines; D000376:Agmatine; D009955:Ornithine Decarboxylase