title: Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture.
abstract: The antiproliferative and proapoptotic properties of melatonin in human colon cancer cells in culture were recently reported. To address the mechanisms involved in these actions, HT-29 human colon cancer cells were cultured in RPMI 1640 medium supplemented with fetal bovine serum at 37 degrees C. Cell proliferation was assessed by the incorporation of [(3)H]-thymidine into DNA. Cyclic nucleotide levels, nitrite concentration, glutathione peroxidase and reductase activities, and glutathione levels were assessed after the incubation of these cells with the following drugs: melatonin membrane receptor agonists 2-iodo-melatonin, 2-iodo-N-butanoyl-5-methoxytryptamine, 5-methoxycarbonylamino-N-acetyltryptamine (GR-135,531), and the antagonists luzindole, 4-phenyl-2-propionamidotetralin, and prazosin; the melatonin nuclear receptor agonist CGP 52608, and four synthetic kynurenines analogs to melatonin 2-acetamide-4-(3-methoxyphenyl)-4-oxobutyric acid, 2-acetamide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid, 2-butyramide-4-(3-methoxyphenyl)-4-oxobutyric acid and 2-butyramide-4-(2-amino-5-methoxyphenyl)-4-oxobutyric acid. The results show that the membrane receptors are not necessary for the antiproliferative effect of melatonin and the participation of the nuclear receptor in this effect is suggested. Moreover, the antioxidative and anti-inflammatory actions of melatonin, counteracting the oxidative status and reducing the production of nitric oxide by cultured HT-29 cells seem to be directly involved in the oncostatic properties of melatonin. Some of the synthetic kynurenines exert higher antiproliferative effects than melatonin. The results reinforce the clinical interest of melatonin due to the different mechanisms involved in its oncostatic role, and suggest a new synthetic pathway to obtain melatonin agonists with clinical applications to oncology.
authors.affiliation: Departamento de Cirugía, Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Navarro
authors.forename: Cristina
authors.initials: C
authors.lastname: González-Puga
authors.forename: Germaine
authors.initials: G
authors.lastname: Escames
authors.forename: Luis C
authors.initials: LC
authors.lastname: López
authors.forename: Ana
authors.initials: A
authors.lastname: López
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Cantarero
authors.forename: Encarnación
authors.initials: E
authors.lastname: Camacho
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Gallo
authors.forename: Darío
authors.initials: D
authors.lastname: Acuña-Castroviejo
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007737:Kynurenine / Q000031:analogs & derivatives / Q000494:pharmacology; D008550:Melatonin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015394:Molecular Structure; D044094:Receptors, Melatonin / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000494:pharmacology; D013882:Thiosemicarbazones / Q000494:pharmacology
chemical_list: D044094:Receptors, Melatonin; D013844:Thiazoles; D013882:Thiosemicarbazones; D007737:Kynurenine; C092451:CGP 52608; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione; D008550:Melatonin